Perspectives in Medicinal Chemistry Current Topics in Medicinal Chemistry, 2019, Vol. 19, No. 26 2375 1873-4294/19 $58.00+.00 © 2019 Bentham Science Publishers PERSPECTIVES IN MEDICINAL CHEMISTRY Perspectives on Anti-Candida Drug Development Ashok K. Dubey 1,* and Rajeev K. Singla 2 1 Department of Biological Sciences & Engineering, Netaji Subhas University of Technology, New Delhi 110078, India; 2 School of Medical & Allied Sciences, KR Mangalam University, Gurugram, India Candidiasis is one of the most common fungal infections. It displays wide ranging manifestations from easily treatable su- perficial infections to life threatening invasive types. The later one is most concerning due to high mortality and morbidity as- sociated with it. Invasive and disseminative candidiasis has been on the rise and was reported to have increased five-folds glob- ally during the past 10-years [1]. Several factors seem to have contributed to the current situation, for example, increase in im- munocompromised population, organ transplant involving immunosuppressive therapy, medical implant devices, patients re- quiring invasive therapy, HIV / AIDS patients, cancer patients on long-term chemotherapy etc. [2, 3]. Other important factor that had led to complexities in the management and treatment of candidemia included emerged and emerging resistance to cur- rent anti-fungal drugs among Candida spp. pathogens. It may be noted that Candida spp. are part of human microbiota, which are acquired early in neonatal life. They colonize mucosal surfaces of oral cavity, gastrointestinal tract and vagina. Host-immune system, aided by healthy human microbiota, maintains the harmless commensal state of Candida spp. However, they are among the prominent opportunistic pathogens and transform themselves into challenging pathogens under favourable conditions. They could invade tissues and may cause sys- temic and blood stream infections. The alarming rise in systemic, invasive, and blood-born candidiasis world over has posed serious threat to human health besides imposing significant economic burden on the states. Thus, it warrants urgent and imme- diate intervention. The transition from commensal to pathogen is attributed to a repertoire of virulence and fitness factors possessed by Can- dida spp. [4]. There are several species of Candida which can cause candidiasis. But five among them are common, which in- cluded C. albicans, C. krusei, C. glabrata, C. tropicalis and C. parapsilosis. Among these, C. albicans is the most commonly associated with the blood stream infection. However, incidences involving non-albicans Candida (NAC) have been on the rise. In addition to the above-mentioned NAC spp., several others had been reported to be the etiological agents of candidiasis [5]. The most significant among these is the multi-drug resistant C. auris, which was first reported in 2009 [6] and has since ac- quired global prevalence in a short span of time. Among the most important fitness attributes of Candida spp. as pathogens are their morphogenesis from yeast cell to hyphal form, and their ability to evade immune defense of the human host [7]. Since decades, primarily three classes of anti-fungal drugs: azoles, echinocandins and polyenes have been employed in the treatment and management of candidiasis. Frequent recurrences of resistance to azoles in Candida spp. have been reported [5]. These pathogens have evolved multiple mechanisms, like, efflux pump to flush out drug, mutations leading to modulation of drug target (lanosterol 14-alpha-demethylase) etc. Further, some of the NAC spp., are inherently resistant to azoles. Echino- candins, which exert their anti-Candida action through inhibition of β-1,3-glucan synthase, happened to be more effective than azoles with much lower incidences of drug resistance against them. However, resistance against echinocandins have also been reported [8, 9]. The polyene, amphotericin B, is usually not the first option drug due to it’s sever side-effects like nephrotoxic- ity. However, it has remained the ‘the gold standard’ for treating disseminative candidiasis. Resistance against amphotericin B is rare, but nonetheless, it has been reported [10, 11]. Cell membrane and cell wall integrity have been the primary targets for these three classes of classical antifungal drugs. However, on account of increasing clinical failure of these drugs in the face of emerging and emerged drug resistance as well as adverse side effects on the host, there is an eminent need to discover and de- velop new anti-fungal drugs including novel classes, which would act on pathogen-specific novel targets enhancing their effi- cacy, and reducing host-toxicity with lower probability of inducing resistance in the pathogens. Another major factor besides the limited inventory of anti-fungal drugs and drug resistance that has complicated the treat- ment and management of invasive candidiasis, has been the emergence of several NAC species which are inherently resistant to the available drugs. C. auris stands out in this regard, which causes infections that present the most significant challenge for treatment. In an attempt to look for novel anti-Candida drugs, critical functions associated with virulence and pathogenicity of the pathogen need to be targeted. Virulence factors, such as, phenotypic switching, the expression of adhesins and invasins on the cell surface, the formation of biofilms, and the secretion of hydrolytic enzymes causing damage to host-cells [12] need to be explored to determine suitable targets for developing new drugs against Candida spp. ____________________________________________ *Address correspondence to this author at the Department of Biological Sciences & Engineering, Netaji Subhas University of Technology, New Delhi 110078, Índia; E-mail: akdubey@nsut.ac.in