Fungal plasma membrane proton pumps as promising new antifungal targets

Fungi are widely dispersed in nature and frequently appear as pathogens in the animal and plant kingdoms. The incidence of opportunistic fungal infections in humans has increased due to the human immunodeficiency virus and the application of modern medical approaches that subvert natural protective barriers to infection. Also, fungal blights continue to threaten crops worldwide. As a result, new antifungal agents are needed to address these critical problems. Existing antifungals can be used to effectively treat most cases of topical infection caused by the opportunistic pathogen Candida albicans, which is the principal agent of nosocomially acquired fungal infections. However, life-threatening, disseminated Candida infections are treated with more modest success. Existing antifungals can be toxic or ineffective because of natural resistance or even induced resistance. This limited efficacy largely reflects the restricted range of cellular targets considered during the development of current antifungals. The advancement of highly selective fungicidal reagents requires the recognition of new essential cellular targets. The fungal plasma-membrane proton pump is a high-abundance essential enzyme with a number of well-understood molecular properties that should facilitate the development of new antifungals. The proton pump is important for intracellular pH regulation and the maintenance of electrochemical proton gradients needed for nutrient uptake. It is a member of the P-type class of ion-transport enzymes, which are present in nearly all external cellular membranes. Typical P-type enzymes such as the Na+,K(+)-ATPase and H+,K(+)-ATPase are well established as specific targets for surface-active cardiac glycosides and anti-ulcer therapeutics. The development of new classes of selective antifungals targeted to the proton pump will require exploitation of the well-characterized genetic, kinetic, topological, regulatory, and drug-interaction features of the fungal enzyme that discriminate it from related host P-type enzymes. New antifungal drugs of this type should be relevant to the control of fungal pathogens of medical and agricultural importance and may be applicable to the control of intracellular parasites that also depend on closely related proton pumps for survival.