Azole Antifungal Resistance in Candida albicans and Emerging Non- albicans Candida Species

Abstract

Within the limited antifungal armamentarium, the azole antifungals are the most frequent class used to treat Candida infections. Azole antifungals such as fluconazole are often preferred treatment for many Candida infections as they are inexpensive, exhibit limited toxicity, and are available for oral administration. There is, however, extensive documentation of intrinsic and developed resistance to azole antifungals among several Candida species. As the frequency of azole resistant Candida isolates in the clinical setting increases, it is essential to elucidate the mechanisms of such resistance in order to both preserve and improve upon the azole class of antifungals for the treatment of Candida infections. This review examines azole resistance in infections caused by C. albicans as well as the emerging non-albicans Candida species C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata and in particular, describes the current understanding of molecular basis of azole resistance in these fungal species.

Keywords: Candida albicans; Candida glabrata; Candida krusei; Candida parapsilosis; Candida tropicalis; antifungal; azole; resistance.

Figure 1

Comparison of documented fluconazole resistance mechanisms in Candida species. (A) Erg3 inactivation results in utilization of alternative sterols in the yeast membrane. (B) Uptake of exogenous sterols helps circumvent endogenous sterol production inhibition by fluconazole. Increased production of both (C) ATP-binding cassette efflux pumps and (D) major facilitator superfamily transporters reduces intracellular accumulation of azoles. (E) Inherently low affinity of fluconazole binding to species-specific Erg11 may decrease fluconazole's potential to inhibit the protein. (F) Increased expression of Erg11 protein can help overcome azole activity and (G) aneuploidy may promote genetic adaptation to azole exposure. (H) Mutations in ERG11 can also result in proteins with reduced affinity for fluconazole binding.