Emerging Virulence, Drug Resistance and Future Anti

Send Orders for Reprints to [email protected] Current Topics in Medicinal Chemistry, 2018, 18, 1-20

1

REVIEW ARTICLE

Emerging Virulence, Drug Resistance and Future Anti-Fungal Drugs for Candida Pathogens Vartika Srivastava, Rajeev Kumar Singla and Ashok Kumar Dubey* Division of Biological Sciences and Engineering, Netaji Subhas Institute of Technology, New Delhi, India

ARTICLE HISTORY Received: December 01, 2017 Revised: February 02, 2018 Accepted: May 18, 2018 DOI: 10.2174/1568026618666180528121707

Abstract: Increased incidences of Candida infection have augmented morbidity and mortality in human population, particularly among severely immunocompromised patients and those having a long stay in hospitals (nosocomial infections). Many virulence factors and fitness attributes are reported to be associated with the pathogenicity of Candida sp. It can cause infections ranging from easily treatable superficial type to life-threatening invasive infections. Additionally, it has the capability to infect humans of all age groups. Indeed, overutilization of broad-spectrum antibiotics has further complicated the scenario by leading the emergence of less sensitive Candida strains especially non-albicans. Despite our developed armamentarium, the diagnosis and treatment of human fungal infections remain a challenge. This review focuses on the prevalence of Candida spp. as human pathogens with emerging resistance to existing anti-fungal drugs. Furthermore, factors and mechanisms contributing to the pathogenicity of Candida spp. and the challenges being faced in combating the devastating infections associated with these pathogens have been discussed. Moreover, pros and cons of the current and future anti-mycotic drugs have been analyzed.

Keywords: Candidemia, Candida pathogenicity, virulence factors, antifungal drugs, antifungal drug resistance. 1. INTRODUCTION Candida spp. are part of human microbiota, residing as commensals in various parts of the human body and they remain innocuous [1, 2]. Factors that make an individual prone to its body’s own normal microflora are immunocompromised situations, long-term use of broad-spectrum antibiotics, and cytotoxic therapies [3, 4]. More than 200 species of Candida have been reported and approximately 65% of them are not pathogenic as they are unable to grow at normal human body temperature and the rest are found to be opportunistic human pathogens [5]. Based on the nature of Candida infection, candidiasis can be of three types: cutaneous, mucosal and systemic (bloodstream infections, i.e., candidemia and other forms of invasive candidiasis [IC]) [6, 7]. In today’s scenario, candidiasis has been reported to be the fourth leading cause of nosocomial bloodstream infections [2, 8]. Mortality rate due to disseminated or systemic candidiasis is reported between 15%49% depending upon the Candida spp. pathogen [4, 9]. Out of all Candida spp., only C. albicans was considered to be the most pathogenic earlier and was responsible for 50-60% cases of invasive candidiasis [10, 11]. However, the percentage of pathogenic non-albicans Candida spp. (NAC) has *Address correspondence to this author at the Division of Biological Sciences and Engineering, Netaji Subhas Institute of Technology, New Delhi, India; Tel: +919205475010; Fax: +911125099022; E-mail: [email protected] 1568-0266/18 $58.00+.00

significantly increased over the past two decades and is reported to be responsible for more than 90% of invasive infections [12]. C. glabrata is found to be multi-drug-resistant (MDR) and candidemia caused by this pathogen is reported to be on the rise [13]. The most frequently isolated NAC from patients in hospitals around the world included C. parapsilosis, C. glabrata, C. krusei and C. tropicalis [14] along with some other NAC spp., for example, C. norvegensis, C. guilliermondii, C. lusitaniae, C. kefyr, C. famata, C. inconspicua, C. rugosa, C. auris and C. dubliniensis [15-17]. The severity of Candida pathogenesis among people has made it an area of extensive research. Although many reviews have been published on this topic, still we found some gaps in the connecting strings of Candida, its pathogenesis and resistance to drugs. In this review, we have presented a detailed update on the prevalence of Candida sp. pathogens, the trend of emerging virulence among them, current antiCandida drugs and resistance against them, and an update on anti-Candida drugs in the pipeline. 2. EMERGING PATTERNS OF SPECIES DISTRIBUTION AND DRUG RESISTANCE AMONG CANDIDA SPP. IN CANDIDIASIS A retrospective study of candidemia at Nantes Hospital (France) was conducted by Tadec et al. during 2004 - 2010 [18]. A total of 197 Candida spp. isolates were identified in 188 patients. C. albicans was the predominant species © 2018 Bentham Science Publishers

2 Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

(52.3%) followed by C. parapsilosis (14.2%), C. glabrata (9.6%), C. tropicalis (9.6%), C. krusei (4.1%) and C. kefyr (2.5%). Other Candida spp. accounted for 7.6% of the isolates and included some rare species such as C. lipolytica, C. inconspicua, C. metapsilosis and C. pelliculosa. Another multicenter surveillance study was conducted by Doi and coworkers in 16 hospitals located across five regions of Brazilto (Brazil) to assess the risk factors for bloodstream infections due to Candida spp. [19]. The study was extensively conducted for 33 months (June 2007 to March 2010). A total of 2,563 nosocomial bloodstream infection (nBSI) episodes were investigated and it was discovered that Candida spp. were the 7th most prevalent pathogens. Most of the patients were male (56 years) and 46.7% among them were in the ICU when candidemia occurred. Malignancies were found to be the most common underlying condition (32%) for nBSI caused by Candida spp. The crude mortality rate due to candidemia during the hospital admission was calculated to be 72.2%. Out of 137 isolated Candida spp., 65.7 % were NAC species. C. albicans was the most frequent isolate (34.3%) followed by C. parapsilosis (24.1%), C. tropicalis (15.3%) and C. glabrata (10.2%). A global trend in distribution of Candida spp. causing candidemia had been published elsewhere [20]. According to the Guinea [20], only five Candida spp. (C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei) accounted for 92% of cases of candidemia. However, their dissemination varied in different geographical regions. C. albicans remained the most frequent pathogen among Candida spp. C. glabrata and C. parapsilosis were the two species whose prevalence varied in different geographical areas. Cases of C. glabrata infections were more predominant in Northern Europe and USA, whereas high prevalence of C. parapsilosis was reported in Spain and Brazil. Furthermore, the global survey also suggested a decrease in frequency for C. albicans infections, consistency in prevalence of C. glabrata and C. krusei while the incidences of C. parapsilosis and C. tropicalis had been increasing [20]. Further epidemiological studies of neonatal and pediatric candidemia in England and Wales during 2000 – 2009 [21] had shown yearly incidence of candidemia to be 1.52/1,00,000 population and the rate was 11/100,000 among infants (under 1 year). Chen and co-workers [22] conducted population-based surveillance studies in Australia during the period 2001- 2004. They reported an yearly candidemia incidence of 1.81 cases per 1,00,000 populations. They also added that the incidence rate was highest among infants (24.8 /1,00,000 population) and among the adults at and above 65 years of age (13.7/100,000 population). Furthermore, infants are more at risk than children and adults. In a global survey undertaken by Pfaller and co-workers [23], it was concluded that invasive candidiasis was not an Intensive Care Unit (ICU)-related infection, and thus non-ICU patients are at equal risk. Around 96% of infections reported both in ICU and non-ICU setups were caused by only five Candida spp.: C. albicans, C. glabrata, C. krusei C. parapsilosis, and C. tropicalis. Among these five species, C. glabrata was found to be resistant to azoles and to echinocandins. In other study also C. glabrata isolates were found to be resistant towards echinocandins (2.4% to anidulafungin and 1.9% to micafungin) and azoles (3.5 to 5.6%) [24]. These resistant strains of Candida pathogens pose a serious threat to human population. The same study also revealed some regional

Srivastava et al.

variations in the prevalence of Candida spp., for example, North American regions were richer in the population of C. glabrata isolates (23.5%). Asian-Pacific regions harbored greater number of C. albicans isolates (56.9%). In Latin American regions, C. parapsilosis (25.6%) and C. tropicalis (17.0%) were reported to be more prevalent. Further, Kaur et al. [25] and Bassetti et al. [26] reported that most of the upcoming cases of candidemia in the ICU patients of India and Italy were due to NAC species. The shift from C. albicans to NAC species in the etiology of candidemia over past 10 years may be a result of diverse medical conditions throughout the world. In case of Brazil, it was reported that 40.9% cases of candidemia were due to C. albicans and 46.3 % involved NAC species [27]. Thus, their potential to cause invasive diseases could be considered to be limited. Some rare NAC species like C. guilliermondii, C. rugose, C. kefyr and C. auris have also been isolated from patients in hospitals and are considered as emerging pathogens world-wide [28-30]. Yet, more detailed study is required to understand their pathogenicity. In order to understand the current scenario of prevalent Candida spp. and their behavior towards antifungal drugs in northeast India, Roy and co-workers [31] did a survey by collecting and analyzing samples from tertiary care hospital. About 113 Candida spp. were isolated, 72.56% were NAC species (32% C. glabrata, 30% C. tropicalis and ~10% others) and 27.43% were C. albicans; antifungal susceptibility testing showed that 36% of the Candida spp. were resistant to fluconazole, 24% of them displayed itraconazole resistance, 21% were found to be voriconazole resistant, and conversely none of the isolates was found to be amphotericin B resistant. However, in a study performed in tertiary care hospitals of India, C. tropicalis, C. glabrata, C. krusei and C. parapsilosis strains were found to be resistant to amphotericin B, fluconazole and itraconazole [32]. 3. PATHOGENICITY AND VIRULENCE ATTRIBUTES OF CANDIDA SPP. The ability of Candida spp. to escape the host immune response plays a significant role in pathogenicity. Several virulence factors and fitness traits attribute to Candida pathogenicity and thus play an important role in establishing diseases [1, 33, 34]. Widely studied virulence factors include adherence, the formation of biofilm, secretion of hydrolytic enzymes, phenotypic plasticity and morphogenesis [1, 3436]. These pathogenicity determinants are governed by Ras/cyclic AMP (cAMP)/protein kinase A (PKA) signal transduction in response to specific combinations of environmental stimuli (contact with catheter materials and exposure to serum or CO2) and cell types. A large number of downstream transcription factors are targeted through this pathway, which further modulates specific set of genes that are involved for the particular determinants [37]. 3.1. Adherence and Biofilm Formation Adhesion of Candida sp. to various host tissues (biological) and medical devices (nonbiological) is a prerequisite for infection, biofilm formation and disease development. The factors involved in the adherence of Candida sp. had been extensively studied and were attributed to the families of proteins responsible for adhesion [34, 38].

Virulence, Drug Resistance and New Anti-Candida Drugs

The adherence of Candida sp. to any biological or nonbiological surfaces is mediated by adhesins. Adhesins are generally glycosylphosphatidylinositol (GPI)-modified cell wall proteins (CWP), also represented as GPI-CWP. At the sequence level, GPI proteins are found to have conserved domains. A highly complex hydrophobic N-terminal domain mediates specific protein-ligand or protein-sugar or other protein-protein interactions and therefore considered as a functional signal sequence. The C-terminal domain is less complex and represents a variable domain, which is usually rich in Ser/Thr and contains tandem repeats which help in cell wall localization [39, 40]. Genes encoding the adhesins in C. albicans include ALS (agglutinin-like-sequence), HWP1 (hyphal wall protein gene), INT1 (integrin-like protein 1) and EAP1 (enhanced adherence to polystyrene protein 1). The ALS gene family encodes cell-surface glycoproteins (adhesins), responsible for adhesion to host surface [41-44]. There are three domains in ALS genes, 5′ domain (approximately 1300 base pairs), central domain (108-base pair tandem repeats) and a Ser/Thr-rich 3′ domain. The regulation of ALS gene is found to be host-site-specific [1, 2, 35, 44, 45]. Proteins such as Als1p expressed by filamenting Candida cells play important role in adherence to human umbilical vein endothelial cells (HUVEC). Als1 mutant cells of Candida sp. displayed reduced filamentation and adherence, consequently reduced virulence. Another member of Als protein family is Als3p (hyphal cell wall protein), present abundantly on germ tube and hyphae surface of C. albicans, it is a key factor in adherence to both HUVEC and buccal epithelial cells (BEC) [46, 47]. It has been reported that Als3p also played important role in invading host cells and tissues, cytokine production, biofilm formation, hydrophobicity and interaction with bacteria like Streptococcus sp. present in oral epithelial cells, resulting in the formation of mixed species biofilms [48]. Hwp1, a CWP is reported to be involved in irreversible adherence to BEC and in biofilm formation [38, 45, 49-51]. The N-terminus domain of Hwp1 is proline and glutaminerich and mediates covalently linking of C. albicans to BEC. Strikingly, Als3p and Hwp1 mutant strains exhibited reduced pathogenicity and virulence in murine models [47, 49, 51, 52]. The EAP1 gene encodes GPI-CWP, which mediated attachment of C. albicans to human epithelial cells and polystyrene surfaces under shear stress, and also mediated biofilm formation. The Efg1 (enhanced filamentous growth 1) mutants of C. albicans did not express EAP1 and showed reduced adherence to HEC (human epithelial cells) [53-55]. The INT1 gene, encoding integrin-like protein (Int1p) and initially characterized as C. albicans adhesion receptor, had a crucial role in attachment to human epithelial cells and also for filamentous growth [53, 56, 57]. Adherence of C. glabrata to host epithelial cells is mediated by adhesin, encoded by the EPA (epithelial adhesion) gene family. The EPA1p is a calcium-dependent lectin, which binds to N-acetyl lactosamine-containing glycol conjugates. Mutation in the Epa1 gene resulted in 95% reduction in the ability of mutants to adhere [35, 38, 58]. Another gene, EPA6, remain silent in vitro but starts expressing in vivo during urinary tract infection (UTI) [5]. In C. dubliniensis and C. tropicalis, ALS gene family has been

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00

3

reported for adhesion but is not identical to that found in C. albicans [5, 41]. In C. parapsilosis, five Als proteins and six PGA 30 (predicted glycosylphosphatidylinositol-anchored protein 30) genes are found to encode for putative cell wall adhesins-like-proteins [5, 59]. Biofilm formed on biological as well as non-biological surfaces is a niche formed by Candida sp. It plays a vital role in their pathogenesis and virulence [1, 36]. Mazaheritehrani and co-workers [60] had presented first in vitro proof that free virus particles (Herpes simplex virus type 1 (HSV-1) and Coxsackie virus type B5 (CVB5) can get embedded in Candida biofilm and can hold its pathogenicity. Thus Candida biofilms can also serve a pool of live viral particles. The formation of biofilm includes the following processes: (1) Attachment of Candida to the host tissues and/or medical devices (e.g. dentures, catheters etc.) through non-specific factors (hydrophobicity and electrostatic forces) and specific factors like adhesins. It can co-aggregate with bacteria present in the host mixed microbial flora. (2) Proliferation of Candida sp. in a self-produced extracellular matrix, which significantly enhances resistance of Candida against antimycotic drugs. (3) Invasion of host tissue, among different morphological forms of Candida, hyphae play the pivotal role in structural integrity and multilayer design of a mature biofilm that further helps Candida to invade the host tissue. (4) Dissemination of cells to various parts of the body through blood [36, 61]. All the above stages of biofilm formation have been found to be regulated by quorum sensing molecules (QSM), which constitute the mechanism of microbial communication [62, 63]. The gene HSP90 (heat shock protein 90) regulates growth, maturation and dispersal of persister cells and is also associated with resistance in Candida against the azole class of antifungal drugs [64]. The transcription factors Bcr1 (biofilm and cell wall regulator 1), Ace2 (activator of CUP1 expression 2), Cph1 (Candida pseudohyphal regulator 1), Czf2 (Candida zinc finger protein 2), Gcn4 (general control nonderepressible 4), Nrg1 (negative regulator of glucose-controlled gene 1), Tec1 (transposon enhancement control 1), Ume6 (unscheduled meiotic gene expression 6), Zap1 (zinc-responsive activator protein 1) and Efg1 (exit from G1); transcription co-activator Spt20 (suppressor of Ty), several genes encoding CWP (Eap1, Hwp1-2, Pga10, Csa1 (Candida surface antigen), Rbt5 (repressed by TUP1 5), Als1-3, Sun41 (Sim1 Uth1 Nca3 4 1) and Ywp1 (yeast-form wall protein 1)), alcohol dehydrogenase (Adh1, Adh5) and aryl-alcohol dehydrogenase (Csh1 (cell surface hydrophobicity 1), Ifd6) are found to be critical determinants of biofilm formation and development in case of C. albicans [65-68]. Mutation in any of these determinants resulted in severe impairments with the formation of biofilm. The development of high level of resistance in the matured biofilm of C. albicans against antifungal drugs: azoles and polyenes, can be explained by the following four points: (1) their ability to persist in low sterol level and also up regulating the genes responsible for ergosterol synthesis, (2) activation of azole efflux genes, CDR1 (Candida drug resistance 1), CDR2 and MDR1 (multidrug resistance 1) in early stage of biofilm formation, (3) presence of persisters (cells tolerant to a range of cidal treatments) in the biofilm and (4) elevated level of β-1,3-glucan in the cell wall and in the surrounding biofilm matrix [66, 69]. Another


unavoidable factor is the QSMs, farnesol and tyrosol. These are morphogenic autoregulatory substances that have a great impact on biofilm development process. Farnesol inhibits Ras1-cyclic AMP signaling pathway that is vital for other cellular processes like stress response and drug resistance [62, 70]. Katragkou et al. have also reported in vitro synergistic interaction of farnesol with three important antifungal drugs: polyenes (amphotericin B), triazoles (fluconazole) and echinicandins (micafungin) against C. albicans biofilm [70]. Tyrosol stimulated formation of the filament in the biofilm [62, 63, 66]. Another molecule, isolated by Hazen and Cutler, having chemical properties different from other QSM, was found to inhibit biofilm development by regulating interconversion of yeast to hyphae form [71]. It was considered as a morphogenic autoregulatory substance (MARS), which suppressed filamentation and expression of hyphaespecific genes in C. albicans [62, 66, 70]. Other QSMs that inhibit hyphal formation are phenylethyl alcohol, dodecanol and nerolidol [66, 72]. C. parapsilosis, C. tropicalis, C. glabrata and C. dubliniensis are reported to be good biofilm producers [73, 74]. When Silva and co-workers compared the biofilms formed by these NAC species, they found that C. parapsilosis and C. tropicalis formed more extensive biofilms [73]. The extracellular matrixes of different Candida spp. differed in the quantity of carbohydrate and protein. The biofilm composition is also affected by the external environmental conditions like pH, oxygen availability and nutrient content in the medium [5, 36]. Several adhesins like Awp2 (adhesin wall protein 2), Awp4, Awp5, Awp6, Epa3 and Epa6, are involved in the biofilm formation in C. glabrata [75]. The expression of CgCDR1 (Candida glabrata Candida drug resistance 1) and CgCDR2 increased during biofilm development in C. glabrata, but their role in azole resistance was found to be doubtful [76]. 3.2. Extracellular Hydrolytic Enzymes Secretory hydrolases play central role in the pathogenesis of Candida sp. This enzyme augments adherence, uptake of extracellular nutrient and active penetration of Candida sp. into the host cells [77, 78]. Secreted aspartyl proteinases, phospholipases, lipases and haemolysins are commonly reported virulence-associated secretory enzymes in Candida spp. [79-81]. 3.2.1 Secretory Aspartyl Proteinases (Saps) It is a family of ten proteinases in C. albicans, which include: Sap1-3 (67% identity), Sap4-6 (89% identity), Sap7 (20-27% identity with other Sap proteins), Sap8 (similar to the clusters formed by Sap1-Sap3 and Sap4-Sap6), Sap9 and Sap10 (similar to the clusters formed by Sap1-Sap3 and Sap4-Sap6). These proteinases are responsible for catalyzing hydrolysis of peptide bonds in the target protein [82, 83]. Among the Saps family, Sap1-Sap8 proteins are secreted extracellularly, whereas Sap9 and Sap10 are anchored in the fungal membrane [82]. A lot of work had been done on Saps in C. albicans and it was found to be associated with a number of virulence factors like hyphae formation, adhesion and phenotypic switching. They also help in digestion of host cell membranes and in evading host immune response by

Srivastava et al.

degrading and inactivating the central human complement components C3b, C4b and C5 [77, 84-86]. SAP genes are widely reported from the Candida spp., for example, SAPT1-SAPT4 and SAPP1-SAPP3 genes were reported from C. tropicalis and C. parapsilosis respectively. In case of C. dubliniensis, SAPCD1-SAPCD4 and SAPCD7SAPCD10 genes were identified [83, 87-89]. The SAP genes of six pathogenic Candida spp. (C. albicans, C. tropicalis, C. parapsilosis, C. dubliniensis, C. lusitaniae, C. guilliermondii) had been analyzed by sequence comparison [90]. On the basis of minimum 50% similarity in the sequences, they have been categorized into 12 families as given in table as: family 1 consisted of SAP1-3 and SAPT4 (C. albicans, C. dubliniensis, C. tropicalis); SAP4-6 was included in family 2 (C. albicans, C. dubliniensis); SAPP1-3 in family 3 (C. parapsilosis); SAPT1 and SAP8 in family 4 (C. albicans, C. dubliniensis, C tropicalis); SAPT2 in family 5 (C. tropicalis); SAPGU and SAPLU were in family 6 (C. guilliermondii, C. lusitaniae); SAPT3 in family 7 (C. tropicalis); C. parapsilosis genes SAPP were grouped in two families: 8 and 9; SAP7 (C. albicans, C. dubliniensis, C. parapsilosis, C. tropicalis) ; SAP10 (C. albicans, C. dubliniensis, C. parapsilosis, C. tropicalis) and SAP9 (C. albicans, C. dubliniensis, C. parapsilosis, C. tropicalis, C. guilliermondii, C. lusitaniae) were considered in families 10, 11, and 12 respectively. The SAP genes of C. albicans and C. dubliniensis were grouped together because they have a very high similarity (>90%). The SAP genes have not been reported from the genomes of C. krusei and C. kefyr till now [83, 90]. 3.2.2. Phospholipases (PL) The enzymes belonging to this family are considered to be integral to the pathogenicity of Candida spp. They hydrolyze phospholipids to fatty acids and thus lead to physical disruption and dysfunction of the host cell membrane. Also, it facilitates adherence of Candida to the host surface [5, 9193]. On the basis of their ability to cleave a specific ester bond, the phospholipases have been categorized into four classes: A, B, C and D. Five members of class B (PLB1-5) contained both, hydrolase and lysophospholipasetransacylase activities [2, 35, 94]. Furthermore, in a study by Ibrahim and co-workers [95], blood isolates and commensal strains were compared for their phospholipase secretion, wherein the isolates from blood were found to be producing more phospholipases than the commensal strains. The clinical isolate of C. albicans, CA30 (invasive strain) showed greater production of extracellular phospholipase than CA87 (non-invasive strain) when tested in a newborn mouse model. These data were further supported by the findings of other workers [35, 96]. It was reported that the NAC species secreted relatively less phospholipases as compared to C. albicans [5, 92, 97, 98]. Few studies have been done on the phospholipases of C. tropicalis and C. parapsilosis, but the findings are not conclusive [89]. 3.2.3. Lipase (LIP) Secretory lipases play vital role in pathogenesis of Candida spp. through the processes like digestion of lipids, adhesion to host cells and tissues, synergistic interactions with other enzymes and nonspecific lipid hydrolysis because of


phospholipolytic activities [99, 100]. Ten members of lipase family, LIP1-10 have been reported [101]. In C. albicans, gene encoding CaLIP8p has major role in virulence. Role of lipases in virulence of NAC species had also been reported. For example, in C. parapsilosis, CpLIP1 and CpLIP2 genes had been identified; CpLIP1-CpLIP2 homozygous mutants were found to develop less complex biofilms and were more prone to attack by macrophage-like cells, thus the mutants were less virulent and less pathogenic than wild type [89]. The lipase producing genes in C. tropicalis had been reported but their role in pathogenesis and virulence had not been studied yet. Furthermore, contrary to the few reports about the presence of lipases in C. tropicalis and C. parapsilosis, no studies had been reported about production of lipase by C. glabrata [5]. Other hydrolytic enzymes, for example, β-Nacetylhexosaminidase (HexNAcase) / N-acetyl-β-D-galactosaminidase (NAGase), acid phosphatase and β-Dglucosidase, were also reported in C. albicans. Mutant strains for NAGase showed decreased virulence when compared to wild C. albicans strains [82, 102,103]. 3.2.4. Hemolysin Haemolytic activity of pathogenic Candida spp. is attributed to hemolysin production. Hemolysins are used to degrade host’s haemoglobin, which served as source of iron for the growth of Candida spp. in the host cells [5, 104]. Hemolysins particularly facilitated hyphal invasion and thus had crucial role in disseminated candidiasis [105, 106]. In a study conducted by Luo et al., fourteen different Candida spp. (eighty isolates) were examined for their haemolytic activity [107]. Both α-haemolytic (partial haemolysis) and βhaemolytic (complete haemolysis) activities were demonstrated by C. albicans, C. dubliniensis, C. kefyr, C. krusei, C. zeylanoides, C. glabrata, C. tropicalis, and C. lusitaniae. However, other strains: C. famata, C. guilliermondii, C. rugosa, and C. utilis displayed only α-Haemolytic activity; whereas C. parapsilosis and C. pelliculosa did not show any haemolytic activity. Further, the expression profile of haemolytic factor among the various species was not constant. Another study by Rossoni and co-workers had also supported the same finding and added some more valuable information [108]. They compared the haemolytic activity between C. albicans and NAC species; out of the fifty strains of different Candida spp. (C. albicans, C. dubliniensis, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, C. dubliniensis, C. norvegensis, C. lusitaniae, and C. guilliermondii), all the strains of C. albicans were found to be producing haemolytic factor, whereas 86% strains of NAC species (except C. guilliermondii and C. parapsilosis) exhibited haemolytic activity. Maximum haemolytic activity was reported in C. glabrata followed by C. albicans. The detailed information about this protein is limited. In C. albicans, however, it is a mannoprotein that ruptures the erythrocytes by binding directly to the cell membrane. This allows the release of iron from haemoglobin, which is taken up by the pathogen [109]. Hemolysin has been poorly studied in NAC strains. Hemolysin-like protein gene (HLP) in C. glabrata and HLPt in C. tropicalis (analogous to HLP in C. glabrata) was analyzed for encoding haemolytic factor [106].


5

3.3. Phenotypic Plasticity Phenotypic switching enables Candida spp. to adapt quickly to the changing environment to be able to survive and to decrease their susceptibility to host defense mechanisms [110, 111]. Switching usually occurs at infection sites to effectively evade the host immune response and to enhance virulence [112-115]. C. albicans has a reversible tristable phenotype switching system that results in white, grey and opaque morphological forms. These cell types differ in their cellular and colony appearances, mating, Sap activities and virulence. Among all the three morphological forms, gray cells exhibit the highest Sap activity and the highest ability to cause cutaneous infections [116]. WOR1 (white-opaque regulator 1) and EFG1 are the master regulator genes of white-gray-opaque cell forms. The WOR1 deletion prevents formation of opaque colonies but permits white-grey switch, alternatively EFG1 deletion stops white cell formation but permit gray-opaque switching [110, 117-119]. Neither WOR1 nor EFG1 are vital for grey phenotype but may together coordinate the regulation of the white-gray-opaque phenotype switching [116]. C. tropicalis exhibits reversible phenotypic switching at a high frequency when grown on yeast extract-peptone-Dglucose (YPD) agar medium. Six different colony morphologies were observed viz. crepe, rough, crater, irregular center, mycelial and diffused [120]. Phenotypic switching in C. tropicalis is dependent on expression of WOR1 gene [118]. C. glabrata can reduce CuSO4 present in agar resulting in brown colored colonies on CuSO4 containing agar plates by upregulating the transcription of metallothionein (MT) genes viz. MTII. They represent two type of phenotype switching systems, “core switching system”, a high frequency and reversible switching to white, light brown, dark brown and very dark brown colonies on CuSO4 containing agar; and “irregular wrinkle switching system”, where cells switch from a core phenotype to irregular wrinkled phenotype [121-123]. C. paripsilosis was explored by Lott and co-workers [124] and Enger and co-workers [125]. They explained the existence of five different phenotypic forms viz. crepe, smooth, concentric, snowball and rough smooth. Laffey and Butler [126] found four different phenotypes viz. crepe, smooth, concentric and crater (fuzzy outline) on YPD medium upon examining 20 clinical isolates of C. paripsilosis. They also added the significance of concentric phenotype in the formation of biofilms [124-126]. The C. dubliniensis isolates exhibited high-frequency phenotypic plasticity more often than the C. albicans isolates [127, 128]. There is a gap in understanding on this aspect of virulence in NAC species. 3.4. Morphogenesis The ability of Candida to grow as budding yeast and in filamentous forms (hyphae and pseudohyphae) complements its virulence and pathogenicity. Hyphal forms are essential for Candida spp. to escape from phagocytes, blood vessels and to colonize on medical devices by forming biofilms [129-132]. In contrast, the yeast form helps in spreading of the pathogen in host tissues [133]. The transition of yeast to hyphal form (Y-H) is regulated by complex signaling path-


ways, various environmental factors like temperature (37 °C), pH (neutral or alkaline) and presence of serum. Lproline and N-acetyl glucosamine (GlcNAc) levels activate this network of signaling pathway [134- 138]. In C. albicans filament-induced genes like HGC (hyphal G cyclin 1), UME6, ALS3, HWP1 and ECE1 (extent of cell elongation 1) are considered as hyphae-specific genes, which are responsible for morphological shift from yeast / pseudohyphal to hyphal morphology [139]. It has been illustrated that signaling pathways like cAMP, mitogen-activated protein kinase (MAPK) and the pH response pathway promotes the transition of C. albicans from budding to hyphal morphogenesis [140]. Additionally, EFG1 plays a central regulator in filamentation process of C. albicans, C. paripsilosis and C. tropicalis [141, 142]. Recently, Naseem and co-workers has illustrated that hyphae-specific gene expression and hyphal morphogenesis can be independently regulated at low ambient pH (∼pH 4). GlcNAc stimulates pH-sensing pathway that is regulated by Rim101 (regulator of IME2 101), which further contributes to the pathogenicity of C. albicans [140]. According to the literature, only C. tropicalis, C. dubliniensis and C. albicans are known to form yeast, pseudohyphae and hyphae; whereas other Candida spp. (C. glabrata, C. lusitaniae, C. guilliermondii and C. parapsilosis) are capable of forming only yeast and pseudohyphae [143].

Srivastava et al.

The amphiphilic structure of the polyene drugs allows them to bind the fungal lipid bilayer and form pores. Nuclear magnetic resonance (NMR) data suggested that eight AmB molecules bind with eight ergosterol molecules through their hydrophobic moieties, with their hydrophilic sides forming a central channel of 70-100 nm in diameter. Pore formation promotes plasma membrane destabilization, and channels allow leakage of intracellular components such as K+ ions and vital cytoplasmic components, leading to the death of organism [147, 149]. Literature also suggested that hydrogen bonding between 2`-OH of AmB and 3β-OH of ergosterol played important role [150].

Fig. (2). Amphotericin B

4. CURRENT DRUGS FOR CANDIDIASIS AND DRUG RESISTANCE AMONG CANDIDA PATHOGENS The therapeutic options available for the treatment of invasive candidiasis and candidemia worldwide are polyenes, azoles, echinocandins and nucleoside analogue [144-146]. But emergence of drug resistant Candida strains has become a major challenge. In the following sections, the antiCandida drugs and resistance mechanisms against them have been discussed.

Fig. (3). Nystatin

4.1. Polyenes These are cyclic amphiphilic organic molecules known as macrolides. Normally they are 20 to 40 carbon macrolactone ring conjugated with a d-mycosamine group. Their amphiphilic properties are due to the presence of several conjugated double bonds on the hydrophobic side of the macrolactone ring, and to the presence of several hydroxyl residues on the opposite, hydrophilic side [147]. They target ergosterol in the fungal cell membrane (Fig. 1). Amphotericin B (AmB; Fig. 2), nystatin (Fig. 3) and natamycin (Fig. 4) are the polyene drugs that are currently under clinical uses [148].

Fig. (1). Cholesterol and Ergosterol, major membrane components of Human and Yeast cells respectively.

Fig. (4). Natamycin

Polyenes possess a lower but non-negligible affinity for cholesterol (Fig. 1), the sterol component in human cell membrane. This is probably because of the double bond in the side chain of ergosterol which restricts the conformation, followed by rigidity in the structure. This slight affinity for cholesterol explains the high toxicity associated with polyenes, which is responsible for severe side effects [147]. AmB is given only systemically, while nystatin (Fig. 3) and natamycin (Fig. 4) are used only locally or orally. Amphotericin B (AmB), a broad-spectrum polyene, still considered as a gold standard for IC and candidemia [151]. AmB deoxycholate (AmB-d) was used for decades for the treatment


of candidiasis, but acute nephrotoxicity has limited its use [152-155]. Other side effects include fever, rigors, and chills during drug infusion [156-158]. In order to improve the therapeutic index of AmB, three new lipid formulations (LFAmB) have been developed and are available in most of the countries. These are: liposomal AmB (L-AmB; AmBiosome), AmB lipid complex (ABLC; Abelcet), and AmB colloidal dispersion (ABCD) [159, 160]. A comparative study suggests that L-AmB may have least renal toxicity [151, 161, 162], but still not completely safe. 4.1.1. Resistance Mechanism Currently, resistance to AmB among Candida spp. is rare or very low. The resistance breakpoints for polyenes have not been determined; in most cases an MIC of ≥1.0 µg/mL indicates resistance to AmB [13, 163]. Polyene resistance is frequently noted in less common species of Candida like C. lusitaniae, C. glabrata, and C. guilliermondii [164-168]. Isolates of C. krusei and C. glabrata are usually resistant to AmB, they show higher MICs to polyenes than C. albicans [8, 169, 170]. The genetic basis for resistance is considered to be the decreased level of or lack of ergosterol content in the cell membranes of polyene-resistant Candida isolates. This could probably happen due to point mutations in ERG3 (ergosterol biosynthesis 3) and ERG6 genes which encode some of the enzymes involved in ergosterol biosynthesis [148, 171, 172]. Another reported mechanism is the increased resistance of strains towards oxidative damage in the cell membrane, through increased production of neutralizing enzymes [173]. Alternatively, high level of AmB resistance in C. albicans biofilms has been associated to differential regulation of ERG1, ERG25, SKN1 (suppressor of Kre null 1), and KRE1 (killer toxin resistant 1) genes [172, 174]. Additionally, a rare missense mutation in CgErg6 gene of C. glabrata leads to poor susceptibility to polyenes [148]. 4.2. Azoles They are cyclic organic molecules representing the largest family of the anti-Candida drugs. They consist of two major groups: the imidazoles which contain two nitrogen atoms (Fig. 5) and the triazoles which contain three nitrogen atoms (Fig. 6) [175]. Miconazole, econazole, clotrimazole, and ketoconazole are the first generation azoles grouped under imidazoles. Fluconazole and itraconazole represent second generation azoles and are grouped under triazoles. The fluconazole derivatives: voriconazole and ravuconazole, and posaconazole (hydroxylated analogue of itraconazole) are third generation azoles [176]. These drugs block the synthesis of ergosterol by inhibiting the activity of the lanosterol 14-"-demethylase encoded by the ERG11 gene and thus resulted into accumulation of sterol intermediates on the cell surface, leading to the inhibition of growth [13, 177-179]. Detailed analysis of the mechanism of action of these azole drugs suggested binding of the free nitrogen atom of the azole ring to the iron atom of the heme group of the enzyme causing inhibition of the fungal pathogen. Ji and co-workers have studied three dimensional model of lanosterol 14-"demethylase, P45014DM or CYP51 of C. albicans. They found that structurally selective residues of the active site of fungal


7

CYP51 are distributed in the C-terminus of F helix, β6-1 sheet and β6-2 sheet [180]. Miconazole was the first approved azole drug, but it was withdrawn from the market due to highly toxic IV formulation. It was replaced by ketoconazole (imidazole) in 1981 for treatment of systemic fungal infections caused by yeasts [181]. However, poor pharmacokinetic properties and some severe side effects such as a decrease in testosterone or glucocorticoids production, liver and gastrointestinal complications associated with imidazoles had resulted in the development of triazoles [182-184]. Davood and Iman had studied the molecular interactions between imidazole and 14αdemethylase (CYP51) and found that azole-heme coordination, π- π as well as π-cation interactions are involved. In the π- π as well as π-cation interactions, aryl moieties of imidazole interact with Phe255 and Arg96 of CYP51 [185]. Fluconazole became available for use by clinicians in 1990 whereas itraconazole was available in 1992 [144, 186]. On the basis of good pharmacokinetic properties as well as its broad spectrum of activity, fluconazole and itraconazole were better tolerated and more effective [187-189]. Voriconazole and posaconazole were approved by FDA in 2002 and 2006, respectively. Ravuconazole is currently under clinical trial phase of drug development. They are more effective against Candida sp. when compared to second generation triazoles, whereas side effects and drug interactions are similar to those observed with fluconazole and itraconazole. Furthermore, fungal pathogens exhibit crossresistance to new generation triazoles [190]. Hargrove and coworkers have studied the molecular mechanism of posaconazole against C. albicans and found that the fluorinated β-phenyl ring of posaconazole was buried deep in the substrate binding cavity and the sixth axial coordination bond with heme iron was formed by the basic nitrogen present in azole ring. Posaconazole interacts with Phe58, Ala61, Ala62, Tyr64, Gly65, Leu88, Tyr118, Leu121, Thr122, Phe126, Ile131, Tyr132, Phe228, Pro230, Phe233, Gly303, Ile304, Gly307, Gly308, Thr311, Leu376, His377, Ser378, Phe380, Tyr505, Ser506, Ser507 and Met508 amino acid residues of C. albicans (PDB: 5TZ1) [191]. However, interaction of azoles with co-administered drugs resulting in severe adverse clinical consequences has placed limitations on the use of fluconazole and itraconazole as antifungal agents [144, 192, 193]. Antifungal drugs of triazole class (voriconazole, posaconazole, itraconazole, and isavuconazole) are commonly used either as first-‐ or second-‐line therapy for treatment of severe fungal infections. Apart from the desired antifungal property, these azole drugs are potent inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, everolimus and sirolimus, along with many other drugs [194, 195]. Thus, co-‐administration of a triazole antifungal drugs with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity [194]. Adverse drug-interactions between vincristine (a drug frequently used in cancer chemotherapy) and itraconazole (and other azoles like: posaconazole, voriconazole and ketoconazole) resulted in toxicity [196]. These severe toxicities are presumed to be related to the inhibitory effects of triazole


drugs on the metabolism of vincristine through the cytochrome P450 (CYP) superfamily of proteins and their transport by P-glycoprotein (P-gp). The adverse effect includes gastrointestinal toxicity, peripheral as well as cranial neuropathy, electrolyte abnormalities and seizures [197].

Srivastava et al.

and itraconazole is believed to be the major reason for resistance [198-201]. NAC like C. glabrata, C. krusei, and C. lusitaniae are found to be intrinsically resistant to fluconazole [8, 202]. The genetic basis for azoles resistance among Candida spp. has been extensively studied [13, 203] and is discussed below: a) Up-regulation of efflux pumps in Candida sp. play a major role in decreasing drug concentration at the enzyme target with in the cell. Efflux pumps are encoded by MDR and CDR genes (multidrug transporter gene) in Candida sp. [168, 204, 205]. In C. albicans azoleresistant is demonstrated by up-regulation of CDR1, CDR2, and MDR1 [206-209]. The genes responsible in C. glabrata is CgCDR1, CgCDR2 and CgSNQ2 (sensitivity to 4-nitroquinoline-N-oxide) gene [210-213]; in C. dubliniensis CdCDR1 and CdMDR1 [214]; besides, CDR1-homologue and ABC (1and 2) genes are found to drive azole resistance in C.tropicalis and C. krusei respectively [215-217]. CDR-encoded efflux pumps are found to be responsible for developing resistance to almost all azole drugs, whereas MDR gene up-regulation is highly selective for fluconazole resistance [13, 168].

Fig. (5). Imidazole class of antifungal drugs: Clotrimazole; Econazole; Miconazole; Ketoconazole.

b) Point mutations in ERG11 gene, encodes CYP (cytochrome P450 lanosterol 14α-demethylase) can results in an altered drug target, which therefore decrease the affinity of azoles drug [209, 218, 219]. This is considered to be the main reason for intrinsic resistance in C. krusei [158]. c) Inactivation of ERG3 gene, involved in the late steps of ergosterol biosynthesis leads to total inactivation of the C-5 sterol desaturase (Erg3p). This leads to the change in the accumulation of type of sterols from 14αmethylergosta-8,24(28)-dien-3β,6α-diol to 14αmethylfecosterol which supports Candida growth [171, 220-222]. d) S279F and S279Y point mutations in C. albicans CYP51 (CaCYP51, 14α-demethylase) leading to the 2 fold increase in affinity towards its substrate i.e. lanosterol. These mutants had 4-5 fold lower affinities for fluconazole, 3.5 fold lower affinities for voriconazole and also 3.5-4.0 lower affinities for itraconazole when compared with the wild strain [223]. 4.2.2. Isavuconazole: Newly launched Triazole

Fig. (6). Triazole class of antifungal drugs: Fluconazole; Itraconazole; Voriconazole; Ravuconazole; and Posaconazole.

4.2.1. Resistance Mechanism The incidence of azole resistance in Candida spp. has increased in the past few years. Extensive use of fluconazole

Isavuconazole (Fig. 7) is a water soluble secondgeneration triazole, with broad-spectrum antifungal activity. It is absorbed easily and can also be administered intravenously in form of a prodrug, known as isavuconazonium sulfate. Isavuconazonium sulfate (marketed as Cresemba), also known as BAL 8557 (Fig. 8), contains an 1-[N-methylN-[3-[2-(methylamino)acetoxymethyl]pyridyn-2yl]aminocarbonyloxy]ethyl substituent attached to the active drug isavuconazole. This portion of the drug is quickly cleaved by plasma esterases or hydrolyzed inside the gastrointestinal lumen releasing the active drug isavuconazole. Isavuconazole (BAL4815) inhibits ergosterol biosynthesis by inhibiting fungal cytochrome P450 lanosterol 14-alpha – demethylase (CYP51). This compound elicits its effects as


fungal cell lysis and death by disturbing synthesis of ergosterol in fungal cell membrane, thereby increasing cell membrane permeability and promoting loss of essential intracellular elements [224, 225]. Isavuconazole has been reported to be active against C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. guilliermondii and C. lusitaniae in vitro [226, 227]. In general, isavuconazole activity against most Candida sp. is comparable to that of voriconazole and posaconazole [228-230]. Around 3000 unique Candida isolates were collected from 2011 and 2012 by the global SENTRY Antimicrobial Surveillance Program, the minimum inhibitory concentration (MIC) values for 90% (MIC90) for all Candida sp., except C. glabrata were ≤1 µg/mL [229, 230]. For most Candida sp., the MIC90 values were ≤0.12 µg/mL; the MIC90 for C. krusei and C. guilliermondii was 1 µg/mL, and for C. glabrata, 2 µg/mL. MIC values for Isavuconazole were ranging from 1 µg/mL to ≥8 µg/mL for C. glabrata isolates which were resistant to other azole drugs like fluconazole and/or voriconazole [230]. It appears that isavuconazole is similar to other azoles in regard to the development of resistance especially in C. glabrata [231]. In phase I studies, isavuconazonium sulfate was administered orally at doses equivalent to 100, 200 and 400 mg of isavuconazole. It was found that the maximum concentration of the drug in plasma was achieved within 1.5 - 3 hours and the t ½ was noted to be 56-77 hours [232]. Intravenous administration at doses equivalent to 50, 100 or 200 mg of isavuconazole resulted in a t ½ of 76-104 hours [232]. Ingestion of meal before administration of the drug had apparently no effect on the bioavailability unlike ravuconazole [233]. Elimination of this drug occurs predominately through the feces, with a small minority of the drug being eliminated via the kidneys [234]. Some adverse effects has also been reported in high-dose group as well as low-dose group, this includes mild-tomoderate headache, rhinitis, back pain, dizziness, cough, abdominal pain, diarrhoea and fatigue [231, 235].

Fig. (7). Isavuconazole, new antifungal triazole.

4.2.3. Echinocandins Echinocandins are a class of semisynthetic drugs derived from lipopeptides. Echinocandins are noncompetitive inhibitors of β-1,3-glucan synthase (GS) required for the synthesis of β-1,3-D-glucan polymers that cover the major component of the fungal cell wall and maintain integrity and rigidity cell wall. Echinocandin inhibit GS by targeting GS FKS (FK506 sensitivity) subunits, which are encoded by, FKS1, FKS2, and FKS3 genes [236-238]. Caspofungin (Cancidas), micafungin (Mycamine), and anidulafungin (Eraxis) are three echinocandins (Fig. 9) that


9

are approved for clinical use [239, 240]. They are preferred over azoles and considered as first line of treatment for candidemia and invasive candidiasis. The reasons for this is, (1) broad spectrum of activity including NAC species, (2) favorable toxicity profiles and (3) reduced cytochrome-mediated drug-drug interactions compared with those of the azoles [240-242]. Caspofungin is used for the treatment of candidemia and invasive candidiasis and other infections for which triazole drugs and even AmB is ineffective. Micafungin is used for treatment of candidemia and fungal infections in bone-marrow transplant patients. Anidulafungin can be used in patients with liver and/or kidney insufficiencies because of its slow degradation in the body without liver or kidney involvement [243]. The main drawback with echinocandins is their poor oral bioavailability, and availability only in form of intravenous therapies [217].

Fig. (8). Isavuconazonium sulfate, prodrug of Isavuconazole.

4.2.3.1. Resistance Mechanism The prevalence of echinocandin resistance in Candida sp. is low. However, reports have been published describing failure of echinocandin treatment. Point mutations in two “hot-spot” regions, HS1 (amino acids at positions 641-649) and HS2 (amino acids at positions 1345-1365) of FKS1 gene [244, 245] can resulted in development of resistance in C. albicans, C. tropicalis, C. krusei and C. glabrata. However, mutation in FKS2 is specifically related to resistance in C. glabrata [146, 246-250]. Other possible mechanism for resistance development are, (1) intrinsic FKS mutations reported in C. parapsilosis and C. guilliermondii, (2) adaptive stress responses at supra minimum inhibitory concentrations (MICs) [251]. 4.2.4. Flucytosine (5-FC) Flucytosine (5-FC) is a synthetic structural analogue of the DNA nucleotide cytosine (Fig. 10). Specific transporters like cytosine permeases or pyrimidine transporters [252] facilitates transport of 5-FC into yeast cell before it gets converted into 5-fluorouracil (5-FU) (Fig. 10) by the cytosine deaminase [253]. Uridine phosphoribosyltransferase (UPRT) helps self-conversion of 5-FU into 5-fluorouracil monophosphate (5-FUMP). The 5-FUMP can then be either converted


into 5-fluorouracil triphosphate, which incorporates into RNA in place of UTP and inhibits protein synthesis, or converted into 5-fluorodeoxyuridine monophosphate, which inhibits a key enzyme of DNA synthesis, the thymidylate synthase, thus inhibiting cell replication [8, 254].

Srivastava et al.

conversion of 5-FC to 5-fluorouracil (5FU) inside the cell and (3) Uracil phosphoribosyltransferase (UPRTase) encoded by the FUR1 gene, helps in rapid conversion of 5-FC to 5-fluorouridine monophosphate (5FUMP) [172, 221, 256]. 5. PRO-DRUGS UNDER CLINICAL TRIALS In view of emerging resistance to antifungal drugs currently in use, there is a greater need than ever before to develop new drugs either as modification to the existing ones or as an entirely new entity. These efforts have led to development of some compounds with desirable drug properties. Such compounds which are currently at clinical trial stage, for example, pro-drugs like, albaconazole, ravuconazole and VT-1161 (phase 2 clinical trials); SCY-078(MK-3118) and T-2307 (phase 1 clinical trials), are being discussed in the following sections [145, 257]. 5.1. Albaconazole Albaconazole is a second-generation triazole also known as UR-9825 (Fig. 11), can be administered topically as well as orally. The mode of action is similar to other antifungal triazoles. Albaconazole was found to be active against filamentous as well as yeast form of fungi [258]. In a study, fluconazole, itraconazole and albaconazole were tested against over 283 Candida sp. On the basis of on MIC90 values, albaconazole was found to show better activity against Candida sp. versus fluconazole and itraconazole. In vitro studies claim its activity on a number of Candida sp. viz. C. albicans, C. parapsilosis, C. tropicalis, C. glabrata, C. krusei and C. guilliermondii [259].

Fig. (9). Echinocandin class of antifungal drugs: Micafungin; Caspofungin and Anidulafungin.

5-FC possesses interesting pharmacokinetic properties due to its high water solubility and small size, 5-FC. Therefore it diffuses rapidly throughout body even when orally administered [12]. It has severe side effects like hepatotoxicity and bone marrow dispersion [254, 255]. 5-FC is frequently used in combination with azoles and AmB; however, monotherapy with 5-FC is not recommended due to resistance development in Candida sp. [217].

Albaconazole is currently being developed as an oral capsule or tablets. It has been studied in several clinical trials including phase I and II studies on Candida vulvovaginitis, tinea pedis and onychomycosis [260]. Albaconazole shows a low toxicity and no serious side effects were reported in clinical studies of albaconazole [261, 262]. Albaconazole when administered at 250 mg/kg q.i.d. or 100 mg/kg b.i.d. every 12 hours for 28 days, a very low toxicity was observed in rats [145]. Albaconazole (400 mg) was well tolerated when taken every 8, 12 or 24 hours for 5 days with general and mild side effects seen in healthy volunteers [263].

Fig. (10). Chemical structures of cytosine, 5-fluorocytosine and 5fluorouracil.

4.2.4.1. Resistance mechanism:

Fig. (11). Albaconazole, second generation antifungal triazole.

Mutation in the genes encoding important enzymes plays a vital role in developing resistance to flucytosine. These enzymes include: (1) purine-cytosine permease (PCP) encoded by the FCY2 (fluorocytosine resistance 2) gene, is required for active transportation of 5-FC is into the cell, (2) cytosine deaminase encoded by the FCY1 gene, mediates

5.2. Ravuconazole A triazole also known as BMS-207147/ER-30346 (Fig. 12), inhibits lanosterol 14α- demethylase, an enzyme involved in sterol synthesis, resulting in the lysis of the fungal cell wall and fungal cell death. It is very similar to isavu-


conazole in structure [264]. Ravuconazole has a long halflife and high protein binding capacity. In vitro studies of ravuconazole demonstrate good anti-Candida activity against C. albicans, C. parapsilosis, C. glabrata, C. tropicalis and C. krusei [145] and found to be 2 - 64 times more active (depending on test species) than itraconazole and fluconazole. Thus, it could be a promising drug for patients infected by itraconazole- and fluconazole-resistant fungi [258]. Oral administration of ravuconazole at 4-10 mg/kg in murine models showed accumulation in plasma at 1.8-2.5 µg/mL and nearly double the concentration in the tissues. An ascending dose trial was conducted in phase I studies, wherein healthy subjects were given ravuconazole as a single dose at 50, 100, 200, 400, 600 or 800 mg [145]. A doseproportional increase for ravuconazole was seen in the plasma of healthy subjects for doses in the range of 50-400 mg, and dose-proportional relationship increase was not seen when the subjects were administered with the drug at over 400 mg. There was an increase in drug bioavailability between 2-4 times when ravuconazole was administered along with the meal having high fat content [145]. During phase II trials, HIV infected patients, afflicted with oropharyngeal candidiasis, were given different doses of ravuconazole (50, 200 and 400 mg) once daily for 5 days, either 2 hours before or after a meal. 85% of the subjects were found to have noticeable improvement in their condition when given a dose of 200 mg for 5 days. Administration of 400 mg once daily was found to be effective for treatment of oropharyngeal candidiasis in the HIV-infected subjects [145]. The main limitation associated with all azole drugs, is cross-resistance. No toxicity was observed in animal studies, whereas some severe adverse effects like head and abdominal pain were noted in humans [265]. Ravuconazole is now being developed as its prodrug, fosravuconazole bis(Llysine) (Fig. 13). Fosravuconazole bis(L-lysine) is under phase III clinical trials for the treatment of fungal infections (onychomycosis) and under phase II clinical trials for treatment of chagas disease.

Fig. (12). Ravuconazole, a second generation antifungal triazole.

5.3. Oteseconazole (VT-1161) Several metalloenzyme inhibitors of fungal lanosterol demethylase (CYP51) have been developed by Viamet Pharmaceuticals (now owned by NovaQuest Capital Management), including VT-1598, VT-1129 and VT-1161. Oral VT-1129 is under preclinical development and active against cryptococcal meningitis. It also targets Candida sp. in vitro and in vivo [197, 266-268]. Oral VT-1161 (Fig. 14) has suc-


11

cessfully completed phase IIb clinical trials targeted for onychomycosis and recurrent vulvovaginal candidiasis.

Fig. (13). Fosravuconazole bis(L-lysine), prodrug of ravuconazole.

VT-1161 is a tetrazole antifungal agent which has potential for the treatment of Candidal vaginal infections. In vitro data demonstrates its activity against C. albicans, C. glabrata and C. parapsilosis [266]. Studies on less susceptible fluconazole isolates of C. albicans (MIC 32 to > 64 mg/L), the MIC values for VT-1161 ranged from ≤ 0.03 to 0.5 mg/L [267]. However, in fluconazole resistant C. albicans isolates (MIC > 64 mg/L), the MIC values for VT-1161 ranged from 0.25 to > 16 mg/L [266]. VT-1161 has also established activity in several murine models of candidiasis [268-270]. In addition, VT-1161 (MIC = 0.002 µg/mL) had a more pronounced fungal sterol disruption profile than the known CYP51 inhibitor, voriconazole (MIC = 0.004 µg/ml) [271]. It also increased survival period and decreased kidney fungal burden in a C. glabrata murine infection model [270]. Additionally, VT-1161 displays very low drug-drug interaction because it shows very less affinity towards human drugmetabolizing CYPs (CYP2C9, CYP2C19, and CYP3A4) [271]. It selectively targets and inhibits C. albicans CYP51 and has very low affinity for human CYP51, demonstrating a >2,000-fold selectivity [271]. Hargrove and co-workers have studied and compared the antifungal drugs like fluconazole, voriconazole, ketoconazole, itraconazole, posaconazole, miconazole, clotrimazole, oteseconazole for their CYP51 inhibitory potential and found that oteseconazole (VT-1161) and posaconazole are the strongest CYP51 inhibitors. Hargrove and coworkers have also studied the molecular mechanism and found that the fluorinated β-phenyl ring of oteseconazole was buried deep in the substrate binding cavity and the sixth axial coordination bond with heme iron was formed by the basic nitrogen present in azole ring. VT-1161 interacted with Tyr64, Tyr118, Leu121, Thr122, Phe126, Ile131, Tyr132, Phe228, Pro230, Phe233, Gly303, Ile304, Gly307, Gly308, Thr311, Leu376, His377, Ser378, Phe380, Tyr505, Ser507 and Met508 amino acid residues of C. albicans (PDB: 5TZ1). Inhibitory potential of oteseconazole was enhanced by the hydrogen bonding between imidazole ring of His377 and trifluoroethoxyphenyl oxygen of oteseconazole [191]. 5.4. SCY-078(MK-3118) It is an oral and parenteral semi-synthetic derivative of enfumafungin, a triterpenoid (Fig. 15). The mode of action


involves inhibition of β-1,3-D-glucan synthase thus preventing appropriate cell wall formation in fungi [272-274]. It is found to be active against C. parapsilosis, C. tropicalis, C. albicans, C. krusei and C. glabrata [275]. In an in vitro study of 113 clinical isolates of Candida sp., MK-3118 and caspofungin was compared for their MIC values, and both had shown similar MIC values against C. parapsilosis (MIC90 0.5 mg/L, for both), C. tropicalis (MIC90 1 mg/L, for both), C. albicans (MIC90 1 mg/L versus 2 mg/L, respectively), and C. krusei (MIC90 2 mg/L versus 1 mg/L, respectively). MK-3118 showed lower MICs than caspofungin against C. glabrata (MIC90 2 mg/L versus 16 mg/L, respectively) [276]. Furthermore, MK-3118 was shown to be active (with an MIC of ≤ 1 mg/L) against 32 out of 34 fluconazole-resistant isolates and was also active (with an MIC of ≤ 1 mg/L) against 22 out of 31 isolates with mutations associated with echinocandin resistance. In contrast, caspofungin was active only against 4 out of 31 such isolates [276]. Study showed potent antifungal activity of SCY-078 against C. auris that expressed several virulence determinants and was resistant to fluconazole and amphotericin B [277]. Additionally, SCY-078 possessed potent anti-biofilm activity, wherein treated biofilms demonstrated significantly reduced metabolic activity and a significantly reduced thickness compared to the untreated control [277]. The available data suggests diarrhoea, cramps and headache to be the most common side effects [257]. This molecule is currently in phase I clinical trials.

Fig. (14). Oteseconazole (VT-1161), a tetrazole based antifungal drug.

Srivastava et al.

Fig. (15). Enfumafungin and its semi-synthetic derivative, SCY078(MK-3118).

5.5. T-2307 It is an arylamidine compound (Fig. 16) available in IV formulations and is under phase I clinical trials. It exerts anti-Candida activity by selectively targeting fungal mitochondria [3]. Its spectrum of activity covers C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis and C. guilliermondii [278]. The compound, T-2307, was also active against C. albicans strains that were not susceptible to fluconazole (MIC 16 to > 64 mg/L) with MIC ranging from 0.0005 to 0.001 mg/L. It also demonstrated potent in vitro activity when administered daily with subcutaneous doses between 0.75 mg/kg and 6 mg/kg of body weight. This led to significant improvement in survival and reduction in fungal burden in mice with invasive candidiasis caused by an echinocandin-resistant strain [279]. Thus, T-2307 may have potential use in the treatment of C. albicans infections caused by strains resistant to fluconazole and echinocandin [278, 279].

Fig. (16). T-2307, an arylamidine antifungal drug.

5.6. CAMB/MAT2203 It is an orally-administered; encochleated formulation of the broad spectrum fungicidal drug amphotericin B. Matinas BioPharma Nanotechnologies, Inc. claims the proprietary for lipid-crystal nano-particle formulation of amphotericin B. This oral formulation is being claimed to have a novel mechanism of absorption and distribution to infected tissues [280-282]. Matinas BioPharma has recently (January, 2018) achieved success in phase IIa clinical study of MAT2203


(orally-administered) for the treatment of chronic refractory mucocutaneous candidiasis. The FDA has designated MAT2203 as a qualified infectious disease product (QIDP) for the treatment of IC, aspergillosis and other invasive fungal infections (commonly seen in immunocompromised patients) [282]. MAT2203 is also being explored by researchers for treatment of additional anti-fungal indications and may have the potential for orphan drug designation in certain of these indications [282]. CONCLUSION The recent reports from epidemiological studies on candidiasis revealed changing pattern of species distribution and their sensitivity to anti-fungal drugs. The rising incidences of non-albicans candidemia and emergence of drug-resistant strains of Candida spp. had continued to undo the good work done in the treatment of immunocompromised, ICU and cancer patients. Efforts to address this issue have led to discovery of several newer antifungal compounds, which are under different stages of development and could be expected to revolutionize the therapy for difficult-to-treat Candida infections. However, these new therapies have important limitations like, their spectrum of activity, pharmacokinetics, risk for pharmacokinetic drug interactions and unusual toxicities associated with long-term use. Antifungal agents like albaconazole, MK-3118/SCY-078, VT-1161 and T-2307 are under clinical trials. A better understanding of pathogenicity mechanisms, host-Candida relationship, anti-Candida immunity and targeting various pathogenic determinants like adherence, biofilm formation, secretory hydrolytic enzymes, dimorphism and heat shock proteins (unique to fungi) can provide novel as well as unambiguous therapeutic targets for treatment of candidaemia. Drug targets like glycosylphosphatidylinositol (GPI) biosynthesis and histone deacetylases should also be explored in order to get more targeted antiCandida drugs [257]. CONSENT FOR PUBLICATION


[6]

[7] [8] [9]

[10] [11] [12]

[13] [14] [15]

[16] [17]

[18]

[19]

Not applicable. CONFLICT OF INTEREST

[20]

The authors declare no conflict of interest, financial or otherwise.

[21]

ACKNOWLEDGEMENTS

[22]

Declared none. REFERENCES [1] [2] [3] [4] [5]

Mayer, F.L.; Wilson, D.; Hube, B. Candida albicans pathogenicity mechanisms. Virulence, 2013, 4, 119-128. Tsaia, P-W.; Chena, Y-T.; Hsu, P-C.; Lan C-Y. Study of Candida albicans and its interactions with the host: a mini review. BioMedicine, 2013, 3, 51-64. Shibata, N.; Kobayashi, H.; Suzuki, S. Immunochemistry of pathogenic yeast, Candida species, focusing on mannan. Proc. Jpn. Acad. Ser. B. Phys. Biol. Sci., 2012, 88, 250-265. Moran, G.P.; Coleman, D.C.; Sullivan, D.J. Candida albicans versus Candida dubliniensis: Why is C. albicans more pathogenic? Int. J. Microbiol., 2012, 2012, 205921. Silva, S.; Negri, M.; Henriques, M.; Oliveira, R.; Williams, D.W.; Azeredo, J. Candida glabrata, Candida parapsilosis and Candida

[23]

[24]

[25]

13

tropicalis: biology, epidemiology, pathogenicity and antifungal resistance. FEMS Microbiol. Rev., 2012, 36, 288-305. Gow, N.A.; van de Veerdonk, F.L.; Brown, A.J.; Netea, M.G. Candida albicans morphogenesis and host defence: discriminating invasion from colonization. Nat. Rev. Microbiol., 2012, 10, 112122. Papon, N.; Courdavault, V.; Clastre, M.; Bennett, R.J. Emerging and emerged pathogenic Candida species: beyond the Candida albicans paradigm. PLoS Pathog., 2013, 9, e1003550. Spampinato, C.; Leonardi, D. Candida infections, causes, targets, and resistance mechanisms: traditional and alternative antifungal agents. BioMed. Res. Int., 2013, 2013, 204237. Cheng, M. F.; Yang, Y.L.; Yao, T.J.; Lin, C.Y.; Liu, J.S.; Tang, R.B.; Yu, K.W.; Fan, Y.H.; Hsieh, K.S.; Ho, M.; Lo, H.J. Risk factors for fatal candidemia caused by Candida albicans and nonalbicans Candida species. BMC Infect. Dis., 2005, 5, 22. Calderone, R.A. Introduction and historical perspectives. In: Candida and candidiasis, R.A. Calderone, Ed.; Washington, DC: ASM Press. 2002; pp. 15-25. Samaranayake, L.P.; Fidel, P.L.; Naglik, J.R.; Sweet, S.P.; Teanpaisan, R.; Coogan, M.M. Blignaut, E.; Wanzala, P. Fungal infections associated with HIV infection. Oral Dis., 2002, 8, 151-160. Pfaller, M.A.; Diekema, D.J.; Procop, G.W.; Rinaldi, M.G. Multicenter comparison of the VITEK 2 antifungal susceptibility test with the CLSI broth microdilution reference method for testing amphotericin B, flucytosine, and voriconazole against Candida spp. J. Clin. Microbiol., 2007, 45, 3522-3528. Pfaller, M.A. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment. Am. J. Med., 2012, 125, S313. MacCallum, D.M. Hosting infection: experimental models to assay Candida virulence. Int. J. Microbiol., 2012, 2012, 363764. Wisplinghoff, H.; Bischoff, T.; Tallent, S.M.; Seifert, H.; Wenzel, R.P.; Edmond, M.B. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin. Infect. Dis., 2004, 39, 309-317. Lopez-Martinez, R. Candidosis, a new challenge. Clin. Dermato., 2010, 28, 178-184. Chowdhary, A.; Sharma, C.; Duggal, S.; Agarwal, K.; Prakash, A.; Singh, P.K.; Jain, S.; Kathuria, S.; Randhawa, H. S.; Hagen, F.; Meis, J. F. New clonal strain of Candida auris, Delhi, India. Emerg. Infect. Dis., 2013, 19, 1670-1673. Tadec, L.; Talarmin, J.P.; Gastinne, T.; Bretonniere, C.; Miegeville, M.; Le Pape, P.; Morio, F. Epidemiology, risk factor, species distribution, antifungal resistance and outcome of candidemia at a single French hospital: a 7‐year study. Mycoses, 2016, 59, 296-303. Doi, A.M.; Pignatari, A.C.; Edmond, M.B.; Marra, A.R.; Camargo, L.F.; Siqueira, R.A.; da Mota, V.P.; Colombo, A.L. Epidemiology and microbiologic characterization of nosocomial candidemia from a Brazilian national surveillance program. PLoS One., 2016, 11, e0146909. Guinea, J. Global trends in the distribution of Candida species causing candidemia. Clin. Microbiol. Infect., 2014, 20, 5-10. Oeser, C.; Lamagni, T.; Heath, P.T.; Sharland, M.; Ladhani, S. The epidemiology of neonatal and pediatric candidemia in England and Wales, 2000-2009. Pediatr. Infect. Dis. J., 2013, 32, 23-26. Chen, S.; Slavin, M.; Nguyen, Q.; Marriott, D.; Playford, E.G.; Ellis, D.; Sorrell, T.; Australian Candidemia Study. Active surveillance for candidemia, Australia. Emerg. Infect. Dis., 2006, 12, 1508-1516. Pfaller, M.A.; Messer, S.A.; Moet, G.J.; Jones, R.N.; Castanheira, M. Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal agents in intensive care unit (ICU) and non-ICU settings in the SENTRY antimicrobial surveillance program (2008–2009). Int. J. Antimicrob. Agents, 2011, 38, 65-69. Pfaller, M.A.; Moet, G.J.; Messer, S.A.; Jones, R.N.; Castanheira, M. Geographic variations in species distribution and echinocandin and azole antifungal resistance rates among Candida bloodstream infection isolates: report from the SENTRY antimicrobial surveillance program (2008 to 2009). J. Clin. Microbiol., 2011, 49, 396399. Kaur, R.; Goyal, R.; Dhakad, M.S.; Bhalla, P.; Kumar R. Epidemiology and virulence determinants including biofilm profile of Candida infections in an ICU in a tertiary hospital in India. J. Mycol., 2014, 2014, 303491.

14 Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00 [26]

[27]

[28] [29]

[30]

[31] [32] [33] [34]

[35] [36]

[37] [38] [39]

[40] [41]

[42] [43] [44] [45]

[46]

Bassetti, M.; Taramasso, L.; Nicco, E.; Molinari, M.P.; Mussap, M.; Viscoli, C. Epidemiology, species distribution, antifungal susceptibility and outcome of nosocomial candidemia in a tertiary care hospital in Italy. PLOS One, 2011, 6, e24198. Colombo, A.L.; Nucci, M.; Park, B.J.; Nouer, S.A.; ArthingtonSkaggs, B.; da Matta1, D.A.; Warnock, D.; Morgan J.; Brazilian Network Candidemia Study. Epidemiology of candidemia in Brazil: a nationwide sentinel surveillance of candidemia in eleven medical centers. J. Clin. Microbiol., 2006, 44, 2816-2823. Lee, W.G.; Shin, J.H.; Uh, Y.; Kang, M.G.; Kim, S.H; Park, K.H.; Jang, H.C. First three reported cases of nosocomial fungemia caused by Candida auris. J. Clin. Microbiol., 2011, 49, 3139-3142. Chowdhary, A.; Anil Kumar, V.; Sharma, C.; Prakash, A.; Agarwal, K.; Babu, R.; Dinesh, K.R.; Karim, S.; Singh, S. K.; Hagen, F.; Meis, J.F. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur. J. Clin. Microbiol. Infect. Dis., 2014, 33, 919926. Dufresne, S.F.; Marr, K.A.; Sydnor, E.; Staab, J.F.; Karp, J.E.; Lu, K.; Zhang, S.X.; Lavallee, C.; Perl, T.M.; Neofytos, D. Epidemiology of Candida kefyr in patients with hematologic malignancies. J. Clin. Microbiol., 2014, 52, 1830-1837. Roy, R.C.; Sharma, G.D.; Barman, S.R.; Chanda, S. Trend of Candida infection and antifungal resistance in a tertiary care hospital of north east India. Afr. J. Microbiol. Res., 2013, 7, 3112-3116. Chander, J.; Singla, N.; Sidhu, S.K.; Gombar, S. Epidemiology of Candida blood stream infections: experience of a tertiary care centre in North India. J. Infect. Dev. Ctries., 2013, 7, 670-675. Hofs, S.; Mogavero, S.; Hube, B. Interaction of Candida albicans with host cells: virulence factors, host defense, escape strategies, and the microbiota. J. Microbiol., 2016, 54, 149-169. Khan, M.S.A.; Ahmad, I.; Aqil, F.; Owais, M.; Shahid, M.; Musarrat, J. Virulence and pathogenicity of fungal pathogens with special reference to Candida albicans. In: Combating Fungal Infections. Ahmad, I.; Owais, M.; Shahid, M.; Aqil, F. Ed.; Springer-Verlag Berlin Heidelberg. 2010, pp. 21-45. Yang, YL. Virulence factor of Candida species. J. Microbiol. Immunol. Infect. 2003, 36, 223-228. Sardi, J.C.; Scorzoni, L.; Bernardi, T.; Fusco-Almeida, A.M.; Mendes Giannini, M.J. Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J. Med. Microbiol., 2013, 62, 10-24. Inglis, D.O.; Sherlock, G. Ras signaling gets fine-tuned: regulation of multiple pathogenic traits of Candida albicans. Eukaryot. Cell., 2013, 12, 1316-1325. Brunke, S.; Hube, B. Two unlike cousins: Candida albicans and C. glabrata infection strategies. Cell Microbiol., 2013, 15, 701-708. De las Penas, A; Pan, S-J.; Castano, I.; Alder, J.; Cregg, R.; Cormack, B.P. Virulence-related surface glycoproteins in the yeast pathogen Candida glabrata are encoded in subtelomeric clusters and subject to RAP1- and SIR-dependent transcriptional silencing. Genes Dev., 2003, 17, 2245-2258. de Groot, P.W.; Bader, O.; de Boer, A.D.; Weig, M.; Chauhan, N. Adhesins in human fungal pathogens: glue with plenty of stick. Eukaryot. Cell, 2013, 12, 470-481. Hoyer, L.L.; Fundyga, R.; Hecht, J.E.; Kapteyn, J.C.; Klis, F.M.; Arnold, J. Characterization of agglutinin-like sequence genes from non-albicans Candida and phylogenetic analysis of the ALS family. Genetics, 2001, 157, 1555-1567. Sundstrom, P. Adhesion in Candida spp. Cell Microbiol., 2002, 4, 461-469. Verstrepen, K.J.; Klis, F.M. Flocculation, adhesion and biofilm formation in yeasts. Mol. Microbiol., 2006, 60, 5-15. Hoyer, L.L.; Green, C.B.; Oh, S.H.; Zhao, X. Discovering the secrets of the Candida albicans agglutinin-like sequence (ALS) gene family--a sticky pursuit. Med. Mycol., 2008, 46, 1-15. Murciano, C.; Moyes, D.L.; Runglall, M.; Tobouti, P.; Islam, A.; Hoyer, L.L.; Naglik, J.R. Evaluation of the role of Candida albicans agglutinin-like sequence (ALS) proteins in human oral epithelial cell interactions. PLoS One, 2012, 7, e33362. Zhao, X.; Oh, S.H.; Cheng, G.; Green, C.B.; Nuessen, J.A.; Yeater, K.; Leng, R.P.; Brown, A.J.; Hoyer, L.L. ALS3 and ALS8 represent a single locus that encodes a Candida albicans adhesin; functional comparisons between Als3p and Als1p. Microbiology, 2004, 150, 2415-2428.

Srivastava et al. [47] [48] [49]

[50]

[51]

[52]

[53] [54] [55]

[56]

[57]

[58] [59]

[60]

[61] [62] [63] [64]

[65]

[66]

Kumamoto, C.A.; Vinces, M.D. Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol., 2005, 7, 1546-1554. Liu, Y.; Filler, S.G. Candida albicans Als3, a multifunctional adhesin and invasin. Eukaryot. Cell, 2011, 10, 168-173. Nobbs, A.H.; Vickerman, M.M.; Jenkinson, H.F. Heterologous expression of Candida albicans cell wall-associated adhesins in Saccharomyces cerevisiae reveals differential specificities in adherence and biofilm formation and in binding oral Streptococcus gordonii. Eukaryot. Cell, 2010, 9, 1622–1634. Wachtler, B.; Wilson, D.; Haedicke, K.; Dalle, F.; Hube, B. From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells. PLoS One, 2011, 6, e17046. Bamford, C.V.; Nobbs, A.H.; Barbour, M.E.; Lamont, R.J.; Jenkinson, H.F. Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with oral bacterium Streptococcus gordonii. Microbiology, 2015; 161, 18-29. Monroy-Perez, E.; Sainz-Espunes, T.; Paniagua-Contreras, G.; Negrete-Abascal, E.; Rodriguez-Moctezuma, J.R.; Vaca, S. Frequency and expression of ALS and HWP1 genotypes in Candida albicans strains isolated from Mexican patients suffering from vaginal candidosis. Mycoses, 2012, 55, e151-157. Li, F.; Palecek, S.P. EAP1, a Candida albicans gene involved in binding human epithelial cells. Eukaryot. Cell, 2003, 2, 1266-1273. Filler, S.G. Candida-host cell receptor-ligand interactions. Curr. Opin. Microbiol., 2006, 9, 333-339. Li, F.; Svarovsky, M.J.; Karlsson, A.J.; Wagner, J.P.; Marchillo, K.;, Oshel, P.; Andes, D.; Palecek, S.P. Eap1p, an adhesin that mediates Candida albicans biofilm formation in vitro and in vivo. Eukaryot. Cell, 2007, 6, 931-939. Kinneberg, K.M.; Bendel, C.M.; Jechorek, R.P.; Cebelinski, E.A.; Gale, C.A.; Berman, J.G.; Erlandsen, S.L.; Hostetter, M.K.; Wells, C.L. Effect of INT1 gene on Candida albicans murine intestinal colonization. J. Surg. Res., 1999, 87, 245-251. Asleson, C.M.; Bensen, E.S.; Gale, C.A.; Melms, A.S.; Kurischko, C.; Berman, J. Candida albicans INT1-induced filamentation in Saccharomyces cerevisiae depends on Sla2p. Mol. Cell Biol., 2001, 21, 1272-1284. Cormack, B.P.; Ghori, N.; Falkow, S. An adhesin of the yeast pathogen Candida glabrata mediating adherence to human epithelial cells. Science, 1999, 285, 578-582. Butler, G., Rasmussen, M.D.; Lin, M.F; Santos, M.A.; Sakthikumar, S.; Munro, C.A.; Rheinbay, E.; Grabherr, M.; Forche, A.; Reedy, J.L.; Agrafioti, I.; Arnaud, M.B.; Bates, S.; Brown, A.J.; Brunke, S.; Costanzo, M.C.; Fitzpatrick, D.A.; de Groot, P.W.; Harris, D.; Hoyer, L.L.; Hube, B.; Klis, F.M; Kodira, C.; Lennard, N.; Logue, M.E.; Martin, R.; Neiman, A.M.; Nikolaou, E.; Quail, M.A; Quinn, J.; Santos, M.C.; Schmitzberger, F.F.; Sherlock, G.; Shah, P.; Silverstein, K.A.; Skrzypek, M.S.; Soll, D.; Staggs, R.; Stansfield, I.; Stumpf, M.P.; Sudbery, P.E.; Srikantha, T.; Zeng, Q.; Berman, J.; Berriman, M.; Heitman, J.; Gow, N.A.; Lorenz, M.C., Birren, B.W.; Kellis, M.; Cuomo, C.A. Evolution of pathogenicity and sexual reproduction in eight Candida genomes. Nature, 2009, 459, 657-662. Mazaheritehrani, E.; Sala, A.; Orsi, C.F.; Neglia, R.G.; Morace, G.; Blasi, E.; Cermelli, C. Human pathogenic viruses are retained in and released by Candida albicans biofilm in vitro. Virus Res., 2014, 179, 153-160. Ramage, G.; Saville, S.P.; Thomas, D.P.; Lopez-Ribot, J.L. Candida biofilms: an update. Eukaryot. Cell, 2005, 4, 633–638. Deveau, A.; Hogan, D.A. Linking quorum sensing regulation and biofilm formation by Candida albicans . Methods Mol. Biol., 2011, 692, 219-233. Albuquerque, P.; Casadevall, A. Quorum sensing in fungi -- a review. Med. Mycol., 2012, 50, 337-345. Robbins, N.; Uppuluri, P.; Nett, J.; Rajendran, R.; Ramage, G.; Lopez-Ribot, J.L.; Andes, D.; Cowen, L.E. Hsp90 governs dispersion and drug resistance of fungal biofilms. PLoS Pathog., 2011, 7, e1002257. Uppuluri, P.; Chaturvedi, A.K.; Srinivasan, A.; Banerjee, M.; Ramasubramaniam, A.K.; Kohler J.R.; Kadosh, D.; Lopez-Ribot, J.L. Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog., 2010, 6, e1000828. Finkel, J.S.; Mitchell, A.P. Genetic control of Candida albicans biofilm development. Nat. Rev. Microbiol., 2011, 9, 109 -118.

Virulence, Drug Resistance and New Anti-Candida Drugs [67] [68]

[69]

[70]

[71] [72]

[73]

[74]

[75]

[76]

[77] [78]

[79] [80] [81]

[82]

[83] [84]

[85] [86]

Fanning, S.; Mitchell, A.P. Fungal biofilms. PLoS Pathog., 2012, 8, e1002585. Tan, X.; Fuchs, B.B.; Wang, Y.; Chen, W.; Yuen, G.J.; Chen, R.B.; Jayamani, E.; Anastassopoulou, C.; Pukkila-Worley, R.; Coleman, J.J.; Mylonakis, E. The role of Candida albicans SPT20 in filamentation, biofilm formation and pathogenesis. PLoS One, 2014, 9, e94468. Nett, J.; Lincoln, L.; Marchillo, K.; Massey, R.; Holoyda, K.; Hoff, B.; VanHandel, M.; Andes, D. Putative role of beta-1,3 glucans in Candida albicans biofilm resistance. Antimicrob. Agents Chemother., 2007, 51, 510-520. Katragkou, A.; McCarthy, M.; Alexander, E.L.; Antachopoulos, C.; Meletiadis, J.; Jabra-Rizk, M.A.; Petraitis, V.; Roilides, E.; Walsh, T.J. In vitro interactions between farnesol and fluconazole, amphotericin B or micafungin against Candida albicans biofilms. J. Antimicrob. Chemother., 2015, 70, 470-478. Hazen, K.C.; Cutler, J.E. Isolation and purification of morphogenic autoregulatory substance produced by Candida albicans. J. Biochem., 1983, 94, 777-783. Martins, M.; Henriques, M.; Azeredo, J.; Rocha, S.M.; Coimbra, M.A.; Oliveira R. Morphogenesis control in Candida albicans and Candida dubliniensis through signaling molecules produced by planktonic and biofilm cells. Eukaryot. Cell, 2007, 6, 2429-2436. Silva, S.; Henriques, M.; Martins, A.; Oliveira, R.; Williams, D.; Azeredo, J. Biofilms of non-Candida albicans Candida species: quantification, structure and matrix composition. Med. Mycol. 2009, 47, 681-689. Villar-Vidal, M.; Marcos-Arias, C.; Eraso, E.; Quindos, G. Variation in biofilm formation among blood and oral isolates of Candida albicans and Candida dubliniensis. Enferm. Infecc. Microbiol. Clin., 2011, 29, 660-665. Kraneveld, E.A.; de Soet, J.J.; Deng, D.M.; Dekker, H.L.; de Koster, C.G.; Klis, F.M.; Crielaard, W.; de Groot, P.W. Identification and differential gene expression of adhesin-like wall proteins in Candida glabrata biofilms. Mycopathologia, 2011,172, 415-427. Song, J.W.; Shin, J.H.; Kee, S.J.; Kim, S.H.; Shin, M.G.; Suh, S.P.; Ryang, D.W. Expression of CgCDR1, CgCDR2, and CgERG11 in Candida glabrata biofilms formed by bloodstream isolates. Med. Mycol., 2009, 47, 545-548. Naglik, J.R.; Challacombe, S.J.; Hube, B. Candida albicans secreted aspartyl proteases in virulence and pathogenesis. Microbiol. Mol. Biol. Rev., 2003, 67, 400-428. Wachtler, B.; Citiulo, F.; Jablonowski, N.; Forster, S.; Dalle, F.; Schaller, M.; Wilson, D.; Hube, B. Candida albicans-epithelial interactions: dissecting the roles of active penetration, induced endocytosis and host factors on the infection process. PLoS One, 2012, 7, e36952. Deorukhkar, S.C.; Saini, S.; Mathew, S. Virulence factors contributing to pathogenicity of Candida tropicalis and its antifungal susceptibility profile. Int. J. Microbiol. 2014, 2014, 456878. Deorukhkar, S.C.; Saini, S.; Mathew, S. Non-albicans Candida infection: an emerging threat. Interdiscip. Perspect. Infect. Dis., 2014, 2014, 615958. Mane, A.; Pawale, C.; Gaikwad, S.; Bembalkar, S.; Risbud, A. Adherence to buccal epithelial cells, enzymatic and hemolytic activities of Candida isolates from HIV-infected individuals. Med. Mycol., 2011, 49, 548-551. Staniszewska, M.; Bondaryk, M.; Siennicka, K.; Piłat, J.; Schaller, M.; Kurzatkowski, W. Role of aspartic proteinases in Candida albicans virulence. part I. substrate specificity of aspartic proteinases and Candida albicans pathogenesis. Post. Mikrobiol., 2012, 51, 127-135. Silva, N.C.; Nery, J.M.; Dias, A.L. Aspartic proteinases of Candida spp.: role in pathogenicity and antifungal resistance. Mycoses, 2014, 57, 1–11. Hube, B.; Hess, D.; Baker, C.A.; Schaller, M.; Schafer, W.; Dolan, J.W. The role and relevance of phospholipase D1 during growth and dimorphism of Candida albicans. Microbiology, 2001, 147, 879-889. Naglik, J.; Albrecht, A.; Bader, O.; Hube, B. Candida albicans proteinases and host/pathogen interactions. Cell Microbiol., 2004, 6, 915-926. Gropp, K.; Schild, L.; Schindler, S.; Hube, B.; Zipfel, P.F.; Skerka, C. The yeast Candida albicans evades human complement attack by secretion of aspartic proteases. Mol. Immun., 2009, 47, 465-475.

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00 [87]

[88] [89] [90]

[91] [92] [93] [94]

[95]

[96] [97]

[98]

[99] [100] [101] [102]

[103]

[104] [105] [106]

[107] [108]

15

Pichova, I.; Pavlickova, L.; Dostal, J.; Dolejsi, E.; HruskovaHeidingsfeldova, O.; Weber, J.; Ruml, T.; Soucek, M. Secreted aspartic proteases of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaniae. inhibition with peptidomimetic inhibitors. Eur. J. Biochem., 2001, 268, 2669-2677. Zaugg, C.; Borg-Von, Z.M.; Reichard, U.; Sanglard, D.; Monod, M. Secreted aspartic proteinase family of Candida tropicalis. Infect. Immun., 2001, 69, 405-412. Trofa. D.; Gacser, A.; Nosanchuk, J.D. Candida parapsilosis, an emerging fungal pathogen. Clin. Microbiol. Rev., 2008, 21, 606625. Parra-Ortega, B.; Cruz-Torres, H.; Villa-Tanaca, L.; HernandezRodriguez, C. Phylogeny and evolution of the aspartyl protease family from clinically relevant Candida species. Mem. Inst. Oswaldo. Cruz., 2009, 104, 505-512. Salyers, A.; Witt, D. Virulence factors that promote colonization In: Bacterial pathogenesis: a molecular approach. Salyers, A.; Witt, D. Ed.; Washington, D.C.: ASM Press. 1994, pp. 30-46. Ghannoum, M.A. Potential role of phospholipases in virulence and fungal pathogenesis. Clin. Microbiol. Rev., 2000, 13, 122-143. Kantarcioglu, A.S.; Yucel, A. Phospholipase and protease activities in clinical Candida isolates with reference to the sources of strains. Mycoses, 2002, 45, 160-165. Mukherjee, P.K.; Chandra, J.; Kuhn, D.M.; Ghannoum, M.A. Differential expression of Candida albicans phospholipase B (PLB1) under various environmental and physiological conditions. Microbiology, 2003, 149, 261-267. Ibrahim, A.S.; Mirbod, F.; Filler, S.G.; Banno, Y.; Cole, G.T.; Kitajima, Y.; Edwards, J.E.; Nozawa, Jr.Y.; Ghannoum, M.A. Evidence implicating phospholipase as a virulence factor of Candida albicans. Infect. Immun., 1995, 63, 1993-1998. Niewerth, M.; Korting, H.C. Phospholipases of Candida albicans. Mycoses, 2001, 44, 361-367. Furlaneto-Maia, L.; Specian, A.F.; Bizerra, F.C.; de Oliveira, M.T.; Furlaneto, M.C. In vitro evaluation of putative virulence attributes of oral isolates of Candida spp. obtained from elderly healthy individuals. Mycopathologia, 2008, 166, 209-217. Galan-Ladero, M.A.; Blanco, M.T.; Sacristan, B.; FernandezCalderon, M.C.; Perez-Giraldo, C.; Gomez-Garcia, A.C. Enzymatic activities of Candida tropicalis isolated from hospitalized patients. Med. Mycol., 2010, 48, 207-210. Stehr, F.; Felk, A.; Kretschmar, M.; Schaller, M.; Schafer, W.; Hube, B. Extracellular hydrolytic enzymes and their relevance during Candida albicans infections. Mycoses, 2000, 43, 17-21. Schaller, M.; Borelli, C.; Korting, H.C.; Hube, B. Hydrolytic enzymes as virulence factors of Candida albicans. Mycoses, 2005, 48, 365-377. Gacser, A.; Stehr, F.; Kroger, C.; Kredics, L.; Schafer, W.; Nosanchuk J.D. Lipase 8 affects the pathogenesis of Candida albicans. Infect. Immun., 2007, 75, 4710-4718. Kanbe,T.; Kurimoto, K.; Hattori, H.; Iwata, T; Kikuchi A. Rapid identification of Candida albicans and its related species Candida stellatoidea and Candida dubliniensis by a single PCR amplification using primers specific for the repetitive sequence (RPS) of Candida albicans. J. Dermatol. Sci., 2005, 40, 43-50. Jacobsen, M.D.; Boekhout, T.; Odds, F.C. Multilocus sequence typing confirms synonymy but highlights differences between Candida albicans and Candida stellatoidea. FEMS Yeast. Res., 2008, 8, 764-770. Manns, J.M.; Mosser, D.M.; Buckley, H.R. Production of a hemolytic factor by Candida albicans. Infect. Immun., 1994, 62, 5154– 5156. Pendrak, M.L.; Yan, S.S.; Roberts, D.D. Sensing the host environment: recognition of haemoglobin by the pathogenic yeast Candida albicans. Arch. Biochem. Bioph., 2004, 426, 148-156. Furlaneto, M.C.; Favero, D.; França, E.J.G.; Furlaneto-Maia, L. Effects of human blood red cells on the haemolytic capability of clinical isolates of Candida tropicalis. J. Biomed. Sci., 2015, 22, 13. Luo, G.; Samaranayake, L.P.; Yau, J.Y. Candida species exhibit differential in vitro hemolytic activities. J. Clin. Microbiol., 2001, 39, 2971–2974. Rossoni, R.D.; Barbosa, J.O.; Vilela, S.F.; Jorge, A.O.; Junqueira, J.C. Comparison of the hemolytic activity between C. albicans and non-albicans Candida species. Braz. Oral Res., 2013, 27, 484-489.


[110] [111]

[112]

[113]

[114]

[115] [116]

[117]

[118]

[119]

[120]

[121]

[122] [123]

[124] [125]

[126] [127]

Watanabe, T.; Takano, M.; Murakami, M.; Tanaka, H.; Matsuhisa, A.; Nakao, N.; Mikami, T.; Suzuki, M.; Matsumoto, T. Characterization of a haemolytic factor from Candida albicans. Microbiology, 1999, 145, 689-694. Morschhauser, J. Regulation of white-opaque switching in Candida albicans. Med. Microbiol. Immunol., 2010, 199, 165-172. Sasse, C.; Hasenberg, M.; Weyler, M.; Gunzer, M.; Morschhauser, J. White-opaque switching of Candida albicans allows immune evasion in an environment-dependent fashion. Eukaryot. Cell, 2013, 12, 50-58. Goldman, D.L.; Fries, B.C.; Franzot, S.P.; Montella, L.; Casadevall A. Phenotypic switching in the human pathogenic fungus Cryptococcus neoformans is associated with changes in virulence and pulmonary inflammatory response in rodents. Proc. Natl. Acad. Sci. USA, 1998, 95, 14967-14972. Kvaal, C.; Lachke, S.A.; Srikantha, T.; Daniels, K.; McCoy, J.; Soll, D.R. Misexpression of the opaque-phase-specific gene PEP1 (SAP1) in the white phase of Candida albicans confers increased virulence in a mouse model of cutaneous infection. Infect. Immun., 1999, 67, 6652-6662. Fries, B.C.; Taborda, C.P.; Serfass, E.; Casadevall, A. Phenotypic switching of Cryptococcus neoformans occurs in vivo and influences the outcome of infection. J. Clin. Invest., 2001, 108, 16391648. Stovicek, V.; Vachova, L.; Begany, M.; Wilkinson, D.; Palkova, Z. Global changes in gene expression associated with phenotypic switching of wild yeast. BMC Genomics, 2014, 15, 136. Tao, L.; Du, H.; Guan, G.; Dai, Y.; Nobile, C.J.; Liang, W.; Cao, C.; Zhang, Q.; Zhong, J.; Huang, G. Discovery of a ‘‘white-grayopaque’’ tristable phenotypic switching system in Candida albicans: roles of non-genetic diversity in host adaptation. PLoS Biol., 2014, 12, e1001830. Lohse, M.B.; Zordan, R.E.; Cain, C.W.; Johnson, A.D. Distinct class of DNA-binding domains is exemplified by a master regulator of phenotypic switching in Candida albicans. Proc. Natl. Acad. Sci. U S A, 2010, 107, 14105-14110. Porman, A.M.; Hirakawa, M.P.; Jones, S.K.; Wang, N.; Bennett, R.J. MTL–independent phenotypic switching in Candida tropicalis and a dual role for Wor1 in regulating switching and filamentation. PLoS Genet., 2013, 9, e1003369. Ramirez-Zavala, B.; Weyler, M.; Gildor, T.; Schmauch, C.; Kornitzer, D.; Arkowitz, R.; Morschhauser. J. Activation of the Cph1dependent MAP kinase signaling pathway induces white-opaque switching in Candida albicans. PLoS Pathog., 2013, 9, e1003696. Moralez, A.T.; França, E.J.; Furlaneto-Maia, L.; Quesada, R.M.; Furlaneto, M.C. Phenotypic switching in Candida tropicalis: association with modification of putative virulence attributes and antifungal drug sensitivity. Med. Mycol., 2014, 52, 106-114. Lachke, S.A.; Srikantha, T.; Tsai, L.K.; Daniels, K.; Soll, D.R. Phenotypic switching in Candida glabrata involves phase-specific regulation of the metallothionein gene MT-II and the newly discovered hemolysin gene HLP. Infect. Immun., 2000, 68, 884–895. Lachke, S.A.; Joly, S.; Daniels, K.; Soll, D.R. Phenotypic switching and filamentation in Candida glabrata. Microbiology, 2002, 148, 2661-2674. Brockert, P.J.; Lachke, S.A.; Srikantha, T.; Pujol, C.; Galask, R.; Soll, D.R. Phenotypic switching and mating type switching of Candida glabrata at sites of colonization. Infect. Immun., 2003, 71, 7109-7118. Lott, T.J.; Kuykendall, R.J.; Welbel, S.F.; Pramanik, A.; Lasker, B.A. Genomic heterogeneity in the yeast Candida parapsilosis. Curr. Genet., 1993, 23, 463–467. Enger, L.; Joly, S.; Pujol, C.; Simonson, P.; Pfaller, M.; Soll, D.R. Cloning and characterization of a complex DNA fingerprinting probe for Candida parapsilosis. J. Clin. Microbiol., 2001, 39, 658669. Laffey, S.F.; Butler, G. Phenotype switching affects biofilm formation by Candida parapsilosis. Microbiology, 2005, 151, 1073-1081. Hannula, J.; Saarela, M.; Dogan, B.; Paatsama, J.; KoukilaKahkola, P.; Pirinen, S.; Alakomi, H.-L.; Perheentupa, J.; Asikainen S. Comparison of virulence factors of oral Candida dubliniensis and Candida albicans isolates in healthy people and patients with chronic candidosis. Oral Microbiol. Immunol., 2000, 15, 238244.

Srivastava et al. [128] [129] [130] [131] [132] [133] [134]

[135]

[136] [137] [138] [139] [140] [141]

[142] [143] [144] [145] [146] [147] [148]

[149]

[150]

[151]

Gutierrez, J.; Morales, P.; Gonzalez, M.A.; Quindos, G. Candida dubliniensis, a new fungal pathogen. J. Basic Microbiol., 2002, 42, 207-227. Phan, Q.T.; Belanger, P.H.; Filler, S.G. Role of hyphal formation in interactions of Candida albicans with endothelial cells. Infect. Immun., 2000, 68, 3485-3490. Lorenz, M.C.; Bender, J.A.; Fink, G.R. Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot. Cell, 2004, 3, 1076-1087. Nobile, C.J.; Mitchell, A.P. Regulation of cell-surface genes and biofilm formation by the C. albicans transcription factor Bcr1p. Curr. Biol., 2005, 15, 1150-1155. Nobile, C.J. Nett, J.E.; Andes, D.R.; Mitchell, A.P. Function of Candida albicans adhesin Hwp1 in biofilm formation. Eukaryot. Cell, 2006, 5, 1604-1610. Sudbery, P.; Gow, N.; Berman, J. The distinct morphogenic states of Candida albicans . Trends Microbiol., 2004, 12, 317-324. Biswas, S.; Van Dijck, P.; Datta, A. Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans. Microbiol. Mol. Biol. Rev., 2007, 71, 348-376. Brown, A.J.P.; Argimon, S.; Gow, N.A.R. Signal transduction and morphogenesis in Candida albicans. In Biology of the fungal cell, 2nd ed.; R.J. Howard & N.A.R. Gow, Ed.; The Mycota VIII. Springer-Verlag, Berlin, Germany. 2007; pp. 167–194 Whiteway, M.; Bachewich, C. Morphogenesis in Candida albicans. Annu. Rev. Microbiol., 2007, 61, 529-553. Ernst, J.F. Transcription factors in Candida albicans - environmental control of morphogenesis. Microbiology, 2000, 146, 17631774. Shareck, J.; Belhumeur, P. Modulation of morphogenesis in Candida albicans by various small molecules. Eukaryot. Cell, 2011, 10, 1004–1012. Fan, Y.; He, H.; Dong, Y.; Pan, H. Hyphae-specific genes HGC1, ALS3, HWP1, and ECE1 and relevant signaling pathways in Candida albicans. Mycopathologia, 2013, 176, 329-335. Naseem, S.; Araya, E.; Konopka, J.B. Hyphal growth in Candida albicans does not require induction of hyphal-specific gene expression. Mol. Biol. Cell., 2015, 26, 1174-1187. Connolly, L.A.; Riccombeni, A.; Grozer, Z.; Holland, L.M.; Lynch, D.B.; Andes, D.R.; Gacser, A.; Butler, G. The APSES transcription factor Efg1 is a global regulator that controls morphogenesis and biofilm formation in Candida parapsilosis. Mol. Microbiol., 2013, 90, 36-53. Mancera, E.; Porman, A.M.; Cuomo, C.A.; Bennett, R.J.; Johnson, A.D. Finding a missing gene: EFG1 regulates morphogenesis in Candida tropicalis. G3 (Bethesda), 2015, 9, 849-856. Thompson, D.S.; Carlisle, P.L.; Kadosh, D. Coevolution of morphology and virulence in Candida species. Eukaryot. Cell, 2011, 10, 1173-1182. Dismukes, W.E. Introduction to antifungal drugs. Clin. Infect. Dis., 2000, 30, 653-657. Pasqualotto, A.C.; Denning, D.W. New and emerging treatments for fungal infections. J. Antimicrob. Chemother., 2008, 61, i19–30. Walker, L.A.; Gow, N.A.; Munro, C.A. Fungal echinocandin resistance. Fungal Genet. Biol., 2010, 47, 117-126. Lemke, A.; Kiderlen, A.F.; Kayser, O. Amphotericin B. Appl. Microbiol. Biotechnol., 2005, 68, 151–162. Vandeputte, P.; Tronchin, G.; Berges, T.; Hennequin, C.; Chabasse, D.; Bouchara, JP. Reduced susceptibility to polyenes associated with a missense mutation in the ERG6 gene in a clinical isolate of Candida glabrata with pseudohyphal growth. Antimicrob. Agents Chemother., 2007, 51, 982-990. Gray, K.C.; Palacios, D.S.; Dailey, I.; Endo, M.M.; Uno, B.E.; Wilcock, B.C.; Burke, M.D. Amphotericin primarily kills yeast by simply binding ergosterol. Proc. Natl. Acad. Sci. U S A., 2012, 109, 2234-2239. Matsumori, N.; Sawada, Y.; Murata, M. Mycosamine orientation of amphoteracin B controlling interaction with ergosterol: steroldependent activity of conformation-restricted derivatives with an amino-carbonyl bridge. J. Am. Chem. Soc., 2005, 127, 1066710675. Van Minnebruggen, G.; Francois, I.E.J.A.; Cammue, B.P.A.; Thevissen, K.; Vroome, V.; Borgers, M.; Shroot, B. A general overview on past, present and future antimycotics. Open Mycol. J., 2010, 4, 22-32.

Virulence, Drug Resistance and New Anti-Candida Drugs [152] [153] [154] [155]

[156] [157] [158] [159] [160]

[161] [162] [163]

[164]

[165] [166] [167] [168] [169]

[170] [171]

[172] [173]

[174]

Fanos, V.; Cataldi, L. Amphotericin B-induced nephrotoxicity: a review. J. Chemother., 2000, 12, 463-470. Deray, G. Amphotericin B nephrotoxicity. J. Antimicrob. Chemother. 2002, 49, 37-41. Laniado-Laborin, R.; Cabrales-Vargas, M.N. Amphotericin B: side effects and toxicity. Rev. Iberoam. Micol., 2009, 26, 223-227. Kagan, S.; Ickowicz, D.; Shmuel, M.; Altschuler, Y.; Sionov, E.; Pitusi, M.; Weiss, A.; Farber, S.; Domb, A.J.; Polacheck, I. Toxicity mechanisms of amphotericin B and its neutralization by conjugation with arabinogalactan. Antimicrob. Agents Chemother., 2012, 56, 5603-5611. Rogers, P.D.; Jenkins, J.K.; Chapman, S.W.; Ndebele, K.; Chapman, B.A.; Cleary, J.D. Amphotericin B activation of human genes encoding for cytokines. J. Infect. Dis., 1998, 178, 1726-1733. Cleary, J.D.; Rogers, P.D.; Chapman, S.W. Variability in polyene content and cellular toxicity among deoxycholate amphotericin B formulations. Pharmacotherapy, 2003, 23, 572-578. Lewis, R.E. Current concepts in antifungal pharmacology. Mayo Clin. Proc., 2011, 86, 805-817. Dupont, B. Overview of the lipid formulations of amphotericin B. J. Antimicrob. Chemother., 2002, 49, 31-36. Pappas, P.G.; Kauffman, C.A.; Andes, D.; Benjamin, D.K.; Calandra, T.F.; Edwards, J.E.; Filler, S.G.; Fisher, J.F.; Kullberg, B-J.; Zeichner, L.O.; Reboli, A.C.; Rex, J.H.; Walsh, T.J.; Sobe, J.D. Clinical practice guidelines for the management candidiasis: 2009 update by the infectious diseases society of America. Clin. Infect. Dis., 2009, 48, 503-535. Wingard, J.R. Lipid formulations of amphotericins: are you a lumper or a splitter? Clin. Infect. Dis., 2002, 35, 891-895. Ellis D. Amphotericin B: spectrum and resistance. J. Antimicrob. Chemother., 2002, 49, 7-10. Tortorano, A.M.; Prigitano, A.; Biraghi, E.; Viviani, M.A. on behalf of the FIMUA-ECMM Candidaemia Study Group. The European confederation of medical mycology (ECMM) survey of Candidaemia in Italy: in vitro susceptibility of 375 Candida albicans isolates and biofilm production. J. Antimicrob. Chemother., 2005, 56, 777-779. Pfaller, M.A.; Messer, S.A.; Hollis, R.J. Strain delineation and antifungal susceptibilities of epidemiologically related and unrelated isolates of Candida lusitaniae. Diagn. Microbiol. Infect. Dis., 1994, 20, 127-133. Martins, M.D.; Rex, J.H. Resistance to antifungal agents in the critical care setting: problems and perspectives. New Horiz., 1996, 4, 338-344. Ghannoum, M.A.; Rice, L.B. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin. Microbiol. Rev., 1999, 12, 501-517. Pappas, P.G.; Rex, J.H.; Sobel, J.D.; Filler, S.G.; Dismukes, W.E.; Walsh, T.J.; Edwards, J.E. Guidelines for treatment of Candidiasis. Clin. Infect. Dis., 2004, 38, 161-189. Kanafani, Z.A. Perfect, J.R. Resistance to antifungal agents: mechanisms and clinical impact. Clin. Infect. Dis, 2008, 46, 120128. Rex, J.H.; Walsh, T.J.; Sobel, J.D.; Filler, S.G.; Pappas, P.G.; Dismukes, W.E.; Edwards, J.E. Practice guidelines for the treatment of candidiasis. infectious diseases society of America. Clin. Infect. Dis., 2000, 30, 662-678. Kontoyiannis, D.P.; Lewis, R.E. Antifungal drug resistance of pathogenic fungi. Lancet, 2002, 359, 1135- 1144. Kelly, S.L.; Lamb, D.C.; Kelly, D.E.; Manning, N.J.; Loeffler, J.; Hebart, H.; Schumacher, U.; Einsele, H. Resistance to fluconazole and cross-resistance to amphotericin B in Candida albicans from AIDS patients caused by defective sterol delta5,6-desaturation. FEBS Lett., 1997, 400, 80-82. Espinel-Ingroff, A. Mechanisms of resistance to antifungal agents: yeasts and filamentous fungi. Rev. Iberoam. Micol., 2008, 25, 101106. Blum, G.; Perkhofer, S.; Haas, H.; Schrettl, M.; Wurzner, R.; Dierich, M.P.; Lass-Florl, C. Potential basis for amphotericin B resistance in Aspergillus terreus. Antimicrob. Agents Chemother., 2008, 52, 1553-1555. Khot, P.D.; Suci, P.A.; Miller, R.L.; Nelson, R.D.; Tyler, B.J. A small subpopulation of blastospores in Candida albicans biofilms exhibit resistance to amphotericin B associated with differential regulation of ergosterol and beta-1,6-glucan pathway genes. Antimicrob. Agents Chemother., 2006, 50, 3708-3716.

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00 [175] [176] [177] [178] [179]

[180]

[181]

[182] [183] [184]

[185] [186] [187] [188] [189]

[190] [191]

[192] [193] [194]

[195]

17

Maertens, J.A. History of the development of azole derivatives. Clin. Microbiol. Infect., 2004, 10, 1–10. Mast, N.; Zheng, W.; Stout, C.D.; Pikuleva, I.A. Antifungal azoles: structural insights into undesired tight binding to cholesterolmetabolizing CYP46A1. Mol. Pharmacol., 2013, 84, 86-94. Hay, R.J. Antifungal drugs. In: European Handbook of Dermatological Treatments, Katsambas AD, Lotti TM. Springer-Verlag Berlin Heidelberg: Springer Berlin Heidelberg, 2003, pp. 700-710. Hof, H. A new, broad-spectrum azole antifungal: posaconazolemechanisms of action and resistance, spectrum of activity. Mycoses, 2006, 49, 2-6. Mishra, N.N.; Prasad, T.; Sharma, N.; Payasi, A.; Prasad, R.; Gupta, D.K.; Singh, R. Pathogenicity and drug resistance in Candida albicans and other yeast species. Acta Microbiol. Immunol. Hung., 2007, 54, 201-235. Ji, H.; Zhang, W.; Zhou, Y.; Zhang, M.; Zhu, J.; Song, Y.; Lu, J.; Zhu, J. A three-dimensional model of lanosterol 14α-demethylase of Candida albicans and its interactions with azole antifungals. J. Med. Chem., 2000, 43, 2493-2505. Heeres, J.; Backx, L.J.J.; Mostmans, J.H.; Van Cutsem, J. Antimycotic imidazoles. part 4. synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent. J. Med. Chem., 1979, 22, 1003-1005. Pont, A.; Williams, P.L.; Loose, D.S.; Feldman, D.; Reitz, R.E.; Bochra, C.; Stevens, D.A. Ketoconazole blocks adrenal steroid synthesis. Ann. Intern. Med., 1982, 97, 370–372. Lewis, J.H.; Zimmerman, H.J.; Benson, G.D.; Ishak, K.G. Hepatic injury associated with ketoconazole therapy. analysis of 33 cases. Gastroenterology, 1984, 86, 503-513. Dismukes, W.E.; Cloud, G.; Bowles, C.; Sarosi, G.A.; Gregg, C.R.; Chapman, S.W.; Scheid, W.M.; Farr, B.; Gallis, H.A.; Marier, R.L.; Karam, G.H.; Bennett, J.E.; Kauffman, C.A.; Medoff, G.; Stevens, D.A.; Kaplowitz, L.G.; Black, J.R.; Roselle, G.A.; Pankey, G.A.; Kerkering, T.M.; Fisher, J.F.; Graybill, J.R.; Shadomy, S. Treatment of blastomycosis and histoplasmosis with ketoconazole: results of a prospective randomized clinical trial. Ann. Intern. Med., 1985, 103, 861-872. Davood, A.; Iman, M. Molecular docking and QSAR study on imidazole derivatives as 14α-demethylase inhibitors. Turk. J. Chem., 2013, 37, 119-133. Hoesley, C.; Dismukes, W.E. Overview of oral azole drugs as systemic antifungal therapy. Semin. Respir. Crit. Care Med., 1997, 18, 301-309. Grant, S.M.; Clissold, S.P. Itraconazole. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs, 1989, 37, 310-344. Grant, S.M.; Clissold SP. Fluconazole. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs, 1990, 39, 877-916. Goa, K.L.; Barradell, L.B. Fluconazole. an update of its pharmacodynamic and pharmacokinetic properties and therapeutic use in major superficial and systemic mycoses in immunocompromised patients. Drugs, 1995, 50, 658-690. Potoski, B.A.; Brown, J. The safety of voriconazole. Clin. Infect. Dis., 2002, 35, 1273–1275. Hargrove, T.Y.; Friggeri, L.; Wawrzak, Z.; Qi, A.; Hoekstra, W.J.; Schotzinger, R.J.; York, J.D.; Guengerich, F.P.; Lepesheva, G.I. Structural analyses of Candida albicans sterol 14α-demethylase complexed with azole drugs address the molecular basis of azolemediated inhibition of fungal sterol biosynthesis. J. Biol. Chem., 2017, 292, 6728-6743. Kauffman, C.A.; Carver, P.L. Use of azoles for systemic antifungal therapy. Adv. Pharmacol., 1997, 39, 143-189. Albengres, E.; Le Louet, H.; Tillement, J.P. Systemic antifungal agents. drug interactions of clinical significance. Drug. Saf., 1998, 18, 83-97. Groll, A.H.; Townsend, R.; Desai, A.; Azie, N.; Jones, M.; Engelhardt, M.; Schmitt-Hoffman, A.H.; Bruggemann, R.J.M. Drug-drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4. Transpl. Infect. Dis., 2017, 19, e12751. Lempers, V.J.; Martial, L.C.; Schreuder, M.F.; Blijlevens, N.M.; Burger, D.M.; Aarnoutse, R.E.; Brüggemann, R.J. Druginteractions of azole antifungals with selected immunosuppressants in transplant patients: strategies for optimal management in clinical practice. Curr. Opin. Pharmacol. 2015, 24, 38-44.


[197]

[198]

[199] [200] [201] [202]

[203] [204]

[205]

[206]

[207]

[208]

[209]

[210]

[211]

[212]

[213]

[214]

Moriyama, B.; Henning, S.A.; Leung, J.; Falade-Nwulia, O.; Jarosinski, P.; Penzak, S.R.; Walsh, T.J. Adverse interactions between antifungal azoles and vincristine: review and analysis of cases. Mycoses, 2012, 55, 290-297. Yang, L.; Yu, L.; Chen, X.; Hu, Y.; Wang, B. Clinical analysis of adverse drug reactions between vincristine and triazoles in children with acute lymphoblastic leukemia. Med. Sci. Monit., 2015, 21, 1656-1661. Goldman, M.; Cloud, G.A.; Smedema, M.; LeMonte, A.; Connolly, P.; McKinsey, D.S. Kauffman, C.A.; Moskovitz, B.; Wheat, L.J. Does long-term itraconazole prophylaxis result in in vitro azole resistance in mucosal Candida albicans isolates from persons with advanced human immunodeficiency virus infection?. Antimicrob. Agents Chemother., 2000, 44, 1585-1587. Hoffman, H.L.; Ernst, E.J.; Klepser, M.E. Novel triazole antifungal agents. Expert Opin. Investig. Drugs, 2000, 9, 593-605. Meis, J.F.; Verweij, P.E. Current management of fungal infections. Drugs, 2001, 61, 13-25. Livermore, D.M. The need for new antibiotics. Clin. Microbiol. Infect., 2004, 10, 1-9. Safdar, A.; van Rhee, F.; Henslee-Downey, J.P.; Singhal, S.; Mehta, J. Candida glabrata and Candida krusei fungemia after highrisk allogeneic marrow transplantation: no adverse effect of lowdose fluconazole prophylaxis on incidence and outcome. Bone Marrow Transplant., 2001, 28, 873-878. Peman, J.; Canton, E.; Espinel-Ingroff, A. Antifungal drug resistance mechanisms. Expert Rev. Anti. Infect. Ther., 2009, 7,453-460. Albertson, G.D.; Niimi, M.; Cannon, R.D.; Jenkinson, H.F. Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance. Antimicrob. Agents Chemother., 1996, 40, 2835– 2841. Sanglard, D.; Ischer, F.; Monod, M.; Bille, J. Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. Microbiology, 1997, 143, 405-416. Sanglard, D.; Kuchler, K.; Ischer, F.; Pagani, J.L.; Monod, M.; Bille J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicrob. Agents Chemother., 1995, 39, 2378-2386. White, T.C. Increased mRNA levels of ERG16, CDR, and MDR1 correlate with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob. Agents Chemother., 1997, 41, 1482-1487. Karababa, M.; Coste, A.T.; Rognon, B.; Bille, J.; Sanglard, D. Comparison of gene expression profiles of Candida albicans azoleresistant clinical isolates and laboratory strains exposed to drugs inducing multidrug transporters. Antimicrob. Agents Chemother., 2004, 48, 3064-3079. MacCallum, D.M.; Coste, A.; Ischer, F.; Jacobsen, M.D.; Odds, F.C.; Sanglard D. Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection. Antimicrob. Agents Chemother., 2010, 54, 1476-1483. Sanglard, D.; Ischer, F.; Bille, J. Role of ATP-binding-cassette transporter genes in high-frequency acquisition of resistance to azole antifungals in Candida glabrata. Antimicrob. Agents Chemother., 2001, 45, 1174-1183. Vermitsky, J.P.; Edlind, T.D. Azole resistance in Candida glabrata: coordinate upregulation of multidrug transporters and evidence for a Pdr1-like transcription factor. Antimicrob. Agents Chemother., 2004, 48, 3773-3781. Torelli, R.; Posteraro, B.; Ferrari, S.; La Sorda, M.; Fadda, G.; Sanglard, D.; Sanguinetti, M. The ATP-binding cassette transporter–encoding gene CgSNQ2 is contributing to the CgPDR1dependent azole resistance of Candida glabrata. Mol. Microbiol., 2008, 68, 186-201. Ferrari, S.; Ischer, F.; Calabrese, D.; Posteraro, B.; Sanguinetti, M.; Fadda, G.; Rohde, B.; Bauser, C.; Bader, O.; Sanglard, D. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog., 2009, 5, e1000268. Sanglard, D.; Bille, J. Current understanding of the modes of action of and resistance mechanisms to conventional and emerging antifungal agents for treatment of Candida infections In: Candida and

Srivastava et al.

[215] [216]

[217] [218] [219]

[220]

[221]

[222]

[223]

[224] [225]

[226]

[227]

[228] [229]

[230]

[231] [232]

candidiasis, Calderone RA Ed.; Washington, DC: ASM Press. 2002, pp. 349-383. Katiyar, S.K.; Edlind, T.D. Identification and expression of multidrug resistance-related ABC transporter genes in Candida krusei. Med. Mycol., 2001, 39, 109-116. Lamping, E.; Ranchod, A.; Nakamura, K.; Tyndall, J.D.; Niimi, K.; Holmes, A.R.; Niimi, M.; Cannon, R.D. Abc1p is a multidrug efflux transporter that tips the balance in favor of innate azole resistance in Candida krusei. Antimicrob. Agents Chemother., 2009, 53, 354-369. Vandeputte, P.; Ferrari, S.; Coste, A.T. Antifungal resistance and new strategies to control fungal infections. Int. J. Microbiol., 2012, 2012, 713687. Noel, T. The cellular and molecular defense mechanisms of the Candida yeasts against azole antifungal drugs. J. Mycol. Med., 2012, 22, 173-178. Xiang, M.J.; Liu, J.Y.; Ni, P.H.; Wang, S.; Shi, C.; Wei, B.; Ni, Y.X.; Ge, H.L. Erg11 mutations associated with azole resistance in clinical isolates of Candida albicans. FEMS Yeast Res., 2013, 13, 386-393. Miyazaki, Y.; Geber, A.; Miyazaki, H.; Falconer, D.; Parkinson, T.; Hitchcock, C.; Grimberg, B.; Nyswaner, K.; Bennett, J.E. Cloning, sequencing, expression and allelic sequence diversity of ERG3 (C5 sterol desaturase gene) in Candida albicans. Gene, 1999, 236, 4351. White, T,C. Mechanisms of resistance to antifungal agents In: Manual of Clinical Microbiology, 9th Ed. Murray, P.R.; Baron, E.J.; Jorgensen, J.H.; Landry, M.L.; Pfaller, M.A. Ed.; Washington, DC: ASM Press. 2007, pp. 1961-1971. Vale-Silva, L.A.; Coste, A.T.; Ischer, F.; Parker, J.E.; Kelly, S.L.; Pinto, E.; Sanglard, D. Azole resistance by loss of function of the sterol Δ5,6-desaturase gene (erg3) in Candida albicans does not necessarily decrease virulence. Antimicrob. Agents Chemother., 2012, 56, 1960 -1968. Warrilow, A.G.S.; Mullins, J.G.L.; Hull, C.M.; Parker, J.E.; Lamb, D.C.; Kelly, D.E.; Kelly, S.L. S279 point mutations in Candida albicans sterol 14-α demethylase (CYP51) reduce in vitro inhibition by fluconazole. Antimicrob. Agents Chemother., 2012, 56, 20992107. Jacobs, S.E.; Petraitis, V.; Small, C.B.; Walsh, T.J. Orphan drugs for the treatment of aspergillosis: focus on isavuconazole. Orphan Drugs: Res. Rev., 2017, 7, 37-46. Rybak, J.M.; Marx, K.R.; Nishimoto, A.T.; Rogers, P.D. Isavuconazole: pharmacology, pharmacodynamics, and current clinical experience with a new triazole antifungal agent. Pharmacotherapy, 2015, 35, 1037-1051. Seifert, H.; Aurbach, U.; Stefanik, D.; Cornely, O. In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates. Antimicrob. Agents Chemother., 2007, 51, 1818-1821. Yamazaki, T.; Inagaki, Y.; Fujii, T.; Ohwada, J.; Tsukazaki, M.; Umeda, I.; Kobayashi, K.; Shimma, N.; Page, M.G.; Arisawa, M. In vitro activity of isavuconazole against 140 reference fungal strains and 165 clinically isolated yeasts from Japan. Int. J. Antimicrob. Agents, 2010, 36, 324-331. Thompson, G.R. III; Wiederhold, N.P. Isavuconazole: a comprehensive review of spectrum of activity of a new triazole. Mycopathologia, 2010, 170, 291–313. Pfaller, M.A.; Messer, S.A.; Rhomberg, P.R.; Jones, R.N.; Castanheira, M. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J. Clin. Microbiol., 2013, 51, 2608-2616. Castanheira, M.; Messer, S.A.; Rhomberg, P.R.; Dietrich, R.R.; Jones, R.N.; Pfaller, M.A. Isavuconazole and nine comparator antifungal susceptibility profiles for common and uncommon Candida species collected in 2012: application of new CLSI clinical breakpoints and epidemiological cutoff values. Mycopathologia, 2014, 178, 1-9. Miceli, M.H.; Kauffman, C.A. Isavuconazole: a new broadspectrum triazole antifungal agent. Clin. Infect. Dis., 2015, 61, 1558-1565. Falci, D.R.; Pasqualotto, A.C. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect. Drug Resist., 2013, 6, 163-174.

Virulence, Drug Resistance and New Anti-Candida Drugs [233] [234] [235]

[236]

[237]

[238] [239] [240]

[241] [242] [243] [244]

[245] [246]

[247]

[248]

[249]

[250]

[251]

Seyedmousavi, S.; Verweij, P.E.; Mouton, J.W. Isavuconazole, a broad-spectrum triazole for the treatment of systemic fungal diseases. Expert Rev. Anti. Infect. Ther., 2015, 13, 9-27. Pettit, N.N.; Carver, P.L. Isavuconazole: a new option for the management of invasive fungal infections. Ann. Pharmacother., 2015, 49, 825-842. Schmitt-Hoffmann, A.; Roos, B.; Maares, J.; Heep, M.; Spickerman, J.; Weidekamm, E.; Brown, T.; Roehrle, M. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob. Agents Chemother., 2006, 50, 286-293. Douglas, C.M.; Foor, F.; Marrinan, J.A.; Morin, N.; Nielsen, J.B.; Dahl, A.M.; Mazur, P.; Baginsky, W.; Li, W.; el-Sherbeini, M. The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc. Natl. Acad. Sci. U S A, 1994, 91, 12907-12911. Bowman, J.C.; Hicks, P.S.; Kurtz, M.B.; Rosen, H.; Schmatz, D.M.; Liberator, P.A.; Douglas, C.M. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob. Agents Chemother., 2002, 46, 3001-3012. Kartsonis, N.A.; Nielsen, J.; Douglas, C.M. Caspofungin: the first in a new class of antifungal agents. Drug Resist. Updat., 2003, 6, 197-218. Denning, D.W. Echinocandin antifungal drugs. Lancet, 2003, 362, 1142-1151. Walker, S.S.; Xu, Y.; Triantafyllou, I.; Waldman, M.F.; Mendrick, C.; Brown, N.; Mann, P.; Chau, A.; Patel, R.; Bauman, N.; Norris, C.; Antonacci, B.; Gurnani, M.; Cacciapuoti, A.; McNicholas, P.M.; Wainhaus, S.; Herr, R.J.; Kuang, R.; Aslanian, R.G.; Ting, P.C.; Black, T.A. Discovery of a novel class of orally active antifungal β-1,3-D-glucan synthase inhibitors. Antimicrob. Agents Chemother., 2011, 55, 5099-5106. Bennett, J.E. Echinocandins for candidemia in adults without neutropenia. N. Engl. J. Med., 2006, 355, 1154-1159. Denning, D.W. Echinocandins: a new class of antifungal. J. Antimicrob. Chemother., 2002, 49, 889-891. Cappelletty, D.; Eiselstein-McKitrick, K. The echinocandins. Pharmacotherapy, 2007, 27, 369-388. Park, S.; Kelly, R.; Kahn, J.N.; Robles, J.; Hsu, M.J.; Register, E.; Li, W.; Vyas, V.; Fan, H.; Abruzzo, G.; Flattery, A.; Gill, C.; Chrebet, G.; Parent, S.A.; Kurtz, M.; Teppler, H.; Douglas, C.M.; Perlin, D.S. Specific substitutions in the echinocandin target Fks1p account for reduced susceptibility of rare laboratory and clinical Candida sp. isolates. Antimicrob. Agents Chemother., 2005, 49, 3264-3273. Perlin, D.S. Resistance to echinocandin-class antifungal drugs. Drug Resist. Updat., 2007, 10, 121-130. Cleary, J.D.; Garcia-Effron, G.; Chapman, S.W.; Perlin, D.S. Reduced Candida glabrata susceptibility secondary to an FKS1 mutation developed during candidemia treatment. Antimicrob. Agents Chemother., 2008, 52, 2263-2265. Garcia-Effron, G.; Lee, S.; Park, S.; Cleary, J.D.; Perlin, D.S. Effect of Candida glabrata FKS1 and FKS2 mutations on echinocandin sensitivity and kinetics of 1,3-β-D-glucan synthase: implication for the existing susceptibility breakpoint. Antimicrob. Agents Chemother., 2009, 53, 3690-3699. Garcia-Effron, G.; Chua, D.J.; Tomada, J.R.; DiPersio, J.; Perlin, D.S.; Ghannoum, M.; Bonilla, H. Novel FKS mutations associated with echinocandin resistance in Candida species. Antimicrob. Agents Chemother., 2010, 54, 2225-2227. Dannaoui, E.; Desnos-Ollivier, M.; Garcia-Hermoso, D.; Grenouillet, F.; Cassaing, S.; Baixench, M.T.; Bretagne, S.; Dromer, F.; Lortholary, O.; French mycoses study group. Candida spp. with acquired echinocandin resistance, France, 2004– 2010. Emerg. Infect. Dis., 2012, 18, 86-90. Alexander, B.D.; Johnson, M.D.; Pfeiffer, C.D.; Jiménez-Ortigosa, C.; Catania, J.; Booker, R.; Castanheira, M.; Messer, S.A.; Perlin, D.S.; Pfaller, M.A. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin. Infect. Dis., 2013, 56, 1724-1732. Beyda, N.D.; Lewis, R.E.; Garey, K.W. Echinocandin resistance in Candida species: mechanisms of reduced susceptibility and therapeutic approaches. Ann. Pharmacother., 2012, 46, 1086-1096.

Current Topics in Medicinal Chemistry, 2018, Vol. 18, No. 00 [252] [253] [254]

[255]

[256]

[257] [258] [259]

[260]

[261]

[262]

[263]

[264] [265]

[266]

[267]

[268]

19

Polak, A.; Grenson, M. Evidence for a common transport system for cytosine, adenine and hypoxanthine in Saccharomyces cerevisiae and Candida albicans. Eur. J. Biochem., 1973, 32, 276–282. Polak, A.; Scholer, H.J. Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy, 1975, 21, 113–130. Vermes, A.; Guchelaar, H.-J.; Dankert, J. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J. Antimicrob. Chemother., 2000, 46, 171-179. Papon, N.; Noel, T.; Florent, M.; Gibot-Leclerc, S.; Jean, D.; Chastin, C.; Villard, J.; Chapeland-Leclerc, F. Molecular mechanism of flucytosine resistance in Candida lusitaniae: contribution of the FCY2, FCY1, and FUR1 genes to 5-fluorouracil and fluconazole cross-resistance. Antimicrob. Agents Chemother., 2007, 51, 369-371. Florent, M.; Noel, T.; Ruprich-Robert, G.; Da Silva, B.; FittonOuhabi, V.; Chastin, C.; Papon, N.; Chapeland-Leclerc, F. Nonsense and missense mutations in FCY2 and FCY1 genes are responsible for flucytosine resistance and flucytosine-fluconazole cross-resistance in clinical isolates of Candida lusitaniae. Antimicrob. Agents Chemother., 2009, 53, 2982-2990. Moriyama, B.; Gordon, L.A.; McCarthy, M.; Henning, S.A.; Walsh, T.J.; Penzak, S.R. Emerging drugs and vaccines for Candidemia. Mycoses, 2014, 57, 718-733. Peyton, L.R.; Gallagher, S.; Hashemzadeh, M. Triazole antifungals: a review. Drugs Today (Barc), 2015, 51, 705-718. Ramos, G.; Cuenca-Estrella, M.; Monzon, A.; RodriguezTudela, J.L. In-vitro comparative activity of UR-9825, itraconazole and fluconazole against clinical isolates of Candida spp. J. Antimicrob. Chemother., 1999, 44, 283-286. Guillon, R.; Pagniez, F.; Picot, C.; Hedou, D.; Tonnerre, A.; Chosson, E.; Duflos, M.; Besson, T.; Loge, C.; Le Pape, P. Discovery of a novel broad-spectrum antifungal agent derived from albaconazole. ACS Med. Chem. Lett., 2013, 4, 288-292. Izquierdo, I.; Lurigados, C.; Perez, I.; Turmo, E.; Ramis, J. First administration into man of UR-9825: a new triazole class of antifungal agent. In: 6th Congress of the European Confederation of Medical Mycology Societies (ECMM), Barcelona, Spain. 2000. Bartroli, X.; Uriach, J. A clinical multicenter study comparing efficacy and tolerability between five single oral doses of albaconazole and fluconazole 150 mg single dose in acute vulvovaginal candidiasis. In: Abstracts of the 45th Interscience Conference on Antimicriobial Agents and Chemotherapy, Washington, DC. Abstract M-722. American Society for Microbiology, Washington, DC, USA 2005. Dietz, A.J.; Barnard, J.C.; van Rossem, K. A randomized, doubleblind, multiple-dose, placebo-controlled, dose escalation study with a 3-cohort parallel group design to investigate the tolerability and pharmacokinetics of albaconazole in healthy subjects. Clin. Pharmacol. Drug Dev. 2014, 3, 25-33. Pasqualotto, A.C.; Thiele, K.O.; Goldani, L.Z. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole. Curr. Opin. Investig. Drugs, 2010, 11, 165-74. Gupta, A.K.; Leonardi, C.; Stoltz, R.R.; Pierce, P.F.; Conetta, B.; Ravuconazole onychomycosis group. A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis. J. Eur. Acad. Dermatol. Venereol., 2005, 19, 437-443. Fothergill, A.W.; Rinaldi, M.G.; Hoekstra, W.J.; Schotzinger, R.J.; Moore, W.R.; Wiederhold, N.P.; Patterson, T.F. In vitro activity of two metalloenzyme inhibitors compared to caspofungin and fluconazole against a panel of 74 Candida spp. Proceedings of the 50th ICAAC meeting, Boston MA, September 12-15, 2010. Fothergill, A.W.; Wiederhold, N.P.; Hoekstra, W.J.; Garvey, E.P.; Schotzinger, R.J.; Moore, W.R.; Patterson, T.F. The fungal Cyp51 inhibitors VT-1161 and VT-1129 maintain in vitro activity against Candida albicans isolates with reduced antifungal susceptibility. Proceedings of the 51st ICAAC meeting, Chicago IL, September 17-20, 2011. Hoekstra, W.J.; O’Leary, A.L.; Moore, W.R.; Schotzinger, R.J. Novel metalloenzyme inhibitors, VT-1161 and VT-1129, exhibit efficacy and survival benefit in a murine systemic candidiasis model, Boston MA, Proceedings of the 50th ICAAC meeting; September 12-15, 2010.


[270]

[271]

[272] [273]

[274]

[275]

[276]

[277]

Najvar, L.K.; Wiederhold, N.P.; Garvey, E.P. Efficacy of the novel fungal Cyp51 inhibitor VT-1161 against invasive candidiasis caused by resistant Candida albicans. Mycoses, 2012, 55(Supp 4), 106, Abstract P036. Garvey, E.P.; O’Leary, A.L.; Hoekstra, W.J.; Moore, R.W.; Schotzinger, R.J. Single or repeat oral doses of the novel CYP51 inhibitor VT-1161 suppress fungal growth and provide a survival benefit in a murine Candida glabrata infection model. Proceedings of the 51st ICAAC meeting, Chicago IL, September 17–20, 2011. Warrilow, A.G.; Hull, C.M.; Parker, J.E.; Garvey, E.P.; Hoekstra, W.J.; Moore, W.R.; Schotzinger, R.J.; Kelly, D.E.; Kelly, S.L. The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob. Agents Chemother., 2014, 58, 7121-7127. Hector, R.F.; Bierer, D.E. New β-glucan inhibitors as antifungal drugs. Expert Opin. Ther. Pat., 2011, 21, 1597–1610. Martins, I.M.; Cortes, J.C.; Munoz, J.; Moreno, M.B.; Ramos, M.; Clemente-Ramos, J.A.; Duran, A.; Ribas, J.C. Differential activities of three families of specific β(1,3)glucan synthase inhibitors in wild-type and resistant strains of fission yeast. J. Biol. Chem., 2011, 286, 3484-96. Onishi, J.; Meinz, M.; Thompson, J.; Curotto, J.; Dreikorn, S.; Rosenbach, M.; Douglas, C.; Abruzzo, G.; Flattery, A.; Kong, L.; Cabello, A.; Vicente, F.; Pelaez, F.; Diez, M.T.; Martin, I.; Bills, G.; Giacobbe, R.; Dombrowski, A.; Schwartz, R.; Morris, S.; Harris, G.; Tsipouras, A.; Wilson, K.; Kurtz, M.B. Discovery of novel antifungal (1,3)-β-D-glucan synthase inhibitors. Antimicrob. Agents Chemother., 2000, 44, 368-77. Lepak, A.J.; Marchillo, K.; Andes, D.R. Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY-078 (MK-3118), using an in vivo murine invasive candidiasis model. Antimicrob. Agents Chemother., 2015, 59, 1265-1272. Pfaller, M.A.; Messer, S.A.; Motyl, M.R.; Jones, R.N.; Castanheira, M. Activity of MK-3118, a new oral glucan synthase inhibitor, tested against Candida spp. by two international methods (CLSI and EUCAST). J. Antimicrob. Chemother., 2013, 68, 858-863. Larkin, E.; Hager, C.; Chandra, J.; Mukherjee, P.K.; Retuerto, M.; Salem, I.; Long, L.; Isham, N.; Kovanda, L.; Borroto-Esoda, K.;

Srivastava et al.

[278]

[279]

[280]

[281]

[282]

Wring, S.; Angulo, D.; Ghannoum, M. The emerging pathogen Candida auris: growth phenotype, virulence factors, activity of antifungals, and effect of SCY-078, a novel glucan synthesis inhibitor, on growth morphology and biofilm formation. Antimicrob. Agents Chemother., 2017, 61, e02396-16. Mitsuyama, J.; Nomura, N.; Hashimoto, K.; Yamada, E.; Nishikawa, H.; Kaeriyama, M.; Kimura, A.; Todo, Y.; Narita, H. In vitro and in vivo antifungal activities of T-2307, a novel arylamidine. Antimicrob. Agents Chemother., 2008, 52, 1318-1324. Wiederhold, N.P.; Najvar, L.K.; Fothergill, A.W.; Bocanegra, R.; Olivo, M.; McCarthy, D.I.; Kirkpatrick, W.R.; Fukuda, Y.; Mitsuyama, J.; Patterson, T.F. The novel arylamidine T-2307 maintains in vitro and in vivo activity against echinocandin-resistant Candida albicans. Antimicrob. Agents Chemother., 2015, 59, 13411343. Anonymous. Safety and efficacy of oral encochleated amphoteracin B (CAMB/MAT2203) in the treatment of vulvovaginal candidiasis. Source: U.S. National Library of Medicine (Clinicaltrials.gov). URL: https://clinicaltrials.gov/ct2/show/NCT02971007 (Accessed May 04, 2018). Anonymous. Matinas BioPharma achieves statistical endpoint for success in Phase 2a clinical study of orally-administered MAT2203 for the treatment of chronic refractory mucocutaneous candidiasis. Source: Globe Newswire. URL: https://globenewswire.com/newsrelease/2018/01/08/1284921/0/en/Matinas-BioPharma-AchievesStatistical-Endpoint-for-Success-in-Phase-2a-Clinical-Study-ofOrally-Administered-MAT2203-for-the-Treatment-of-ChronicRefractory-Mucocutaneous-Candidia.html (Accessed May 04, 2018). Matinas BioPharma achieves statistical endpoint for success in Phase 2a clinical study of orally-administered MAT2203 for the treatment of chronic refractory mucocutaneous candidiasis. Source: Matinas Biopharma. URL: https://www.matinasbiopharma.com/media/pressreleases/detail/303/matinas-biopharma-achieves-statisticalendpoint-for-success. (Accessed May 04, 2018).

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.