Membrane transporters and antifungal drug resistance

Over the last 30 years or so, the incidence of invasive fungal infections in man has risen dramatically. Patients that become severely immunocompromised because of underlying diseases such as leukemia or recently, acquired immunodeficiency syndrome or patients who undergo cancer chemotherapy or organ transplantation, are particularly susceptible to opportunistic fungal infections. Although Candida species continue to be the major pathogenic fungi in these patients, cryptococcosis, aspergillosis, and coccidioidomycosis, among others, have become increasingly important mycoses. Antifungal drugs currently being used in clinic include polyene antibiotics, azole derivatives and 5-fluorocytosine. With the exception of the latter, all other drugs possess mechanisms of action aimed at disrupting the integrity of the fungal cell membrane by either interfering with the biosynthesis of membrane sterols or by inhibiting sterol functions. However, one significant obstacle preventing successful antifungal therapy is the dramatic increase in drug resistance, especially against azole antimycotics. Among the major mechanisms by which fungi invoke drug resistance is the overexpession of extrusion pumps able to facilitate the efflux of cytotoxic drugs from the cell thus leading to decreased drug accumulation and diminished concentrations. Since the initial observations that azole resistance by fungi may be caused by overexpression of multidrug efflux transporter genes, significant advances have been achieved primarily with Saccharomyces cerevisiae and Candida albicans. The purpose of this review is to discuss various aspects of multidrug resistance in fungi such as antifungal drug mechanisms of action and fungal molecular genetics in the context of targeted drug discovery. The role that membrane transporter proteins play in drug resistance in various species of Candida, Aspergillus and Cryptococcus will be address in more detail, as will be their importance as selective drug targets in the design of novel antifungal agents.