An update on antifungal targets and mechanisms of resistance inCandidaalbicans

Abstract

Much progress has been made in the last decade in identifying genes responsible for antifungal resistance in Candida albicans. Attention has focused on five major C. albicans genes: ABC transporter genes CDR1 and CDR2, major facilitator efflux gene MDR1, and ergosterol biosynthesis genes ERG11 and ERG3. Resistance involves mutations in 14C-lanosterol demethylase, targeted by fluconazole (FLZ) and encoded by ERG11, and mutations that up-regulate efflux genes that probably efflux the antifungals. Mutations that affect ERG3 mutations have been understudied as mechanism resistance among clinical isolates. In vitro resistance in clinical isolates typically involves step-wise mutations affecting more than one of these genes, and often unidentified genes. Different approaches are needed to identify these other genes. Very little is understood about reversible adaptive resistance of C. albicans despite its potential clinical significance; most clinical failures to control infections other than oropharyngeal candidiasis (OPC) occur with in vitro susceptible strains. Tolerance of C. albicans to azoles has been attributed to the calcineurin stress-response pathway, offering new potential targets for next generation antifungals. Recent studies have identified genes that regulate CDR1 or ERG genes. The focus of this review is C. albicans, although information on Saccharomyces cerevisiae or Candida glabrata is provided in areas in where Candida research is underdeveloped. With the completion of the C. albicans genomic sequence, and new methods for high throughput gene overexpression and disruption, rapid progress towards understanding the regulation of resistance, novel resistance mechanisms, and adaptive resistance is expected in the near future.