Abstract
Antifungal resistance at the gene level has been studied in C. albicans for about a decade now. Cloning of C. albicans genes by homology to resistance genes in S. cerevisiae, and heterologous expression of C. albicans genes in S. cerevisiae has allowed rapid progress in identifying and studying the five major C. albicans genes involved in resistance to clinically used antifungals: ABC transporter genes CDR1 and CDR2, major facilitator efflux gene MDR1, and ergosterol biosynthesis genes ERG11 and ERG3. Analysis of these genes indicates that resistance involves alterations to the enzyme targeted by FLZ, encoded by ERG11, and upregulation of P-glycoprotein-type ABC transporters and major facilitators (MFS) that probably efflux azoles, terbinafine, and perhaps caspofungin. Potential alterations to ERG3 or its regulation have been understudied in C. albicans. Resistant isolates from clinical samples, especially in oropharyngeal candidiasis (OPC), typically display stepwise mutations in more than one of these genes. However, it is clear from in vivo and in vitro studies that mutations of these major genes do not completely account for the evolution of high-level azole resistance in some clinical isolates. More work is needed that is independent of heterologous studies in S. cerevisiae, to identify other genes that contribute to resistance in C. albicans. Very little is understood about reversible, adaptive resistance of C. albicans, despite its potential clinical significance. Most clinical failures to control non-OPC infections occur with in vitro-susceptible strains. There has been important discovery of tolerance mechanisms to azoles. Heterologous studies in S. cerevisiae on regulation of target genes have been less useful, due to differences in regulation in C. albicans. Nevertheless, recent has progress has been made in identifying genes that regulate CDR1 or ERG genes.
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Akins, R.A., Sobel, J.D. (2017). Antifungal Targets, Mechanisms of Action, and Resistance in Candida albicans . In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_30
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