The ins and outs of azole antifungal drug resistance: Molecular mechanisms of transport

Azoles are a major class of antifungal drugs commonly used to treat pathogenic fungi. Azole antifungals are relatively inexpensive, share similar chemical structures, and are effective against most fungal species. Azoles target a crucial enzyme in the ergosterol biosynthesis pathway whose inhibition leads to reduced fungal growth. Azole treatment, combined with the host’s immune system, results in the elimination of the fungus fromthe host. Since azoles are fungistatic instead of fungicidal, their prolonged use and abuse often results in the development of resistance, which is a serious clinical problem in antifungal therapy. The main mechanisms by which fungi become resistant to azoles are increased efflux of the drug from the fungal cell, and modifications in the sterol biosynthesis pathway, especially in the azole target enzyme. In general, all known fungal pathogens share these two basic types of resistance mechanisms, although the specific efflux pumps or mutations in the sterol pathway may be unique for each fungus. This chapter summarizes the development of azole resistance in the major human fungal pathogen, Candida albicans, and compares these mechanisms to those in other fungal pathogens. Resistance to other non-azole antifungal drugs is also discussed.