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F ungal pathogens are notoriously difficult to treat because of antifungal drug toxicity and drug resistance, and the limited armamentarium (1). Some drug classes inhibit fungal growth but do not efficiently eliminate pathogens, and there is a pressing need for advances in antifungal therapy. The problem is especially acute in the immunocompromised. In a recent issue of PNAS, Cowen et al. (2) describe how harnessing heat shock protein 90 (Hsp90) dramatically enhances the efficacy of available antifungal drugs and provides a powerful new avenue for eradicating fungal infections. Hsp90 is an essential chaperone responsible for folding and maturation of client proteins. These include signal transducers with unstable conformations that only acquire their active structure in response to specific signals. Moreover, Hsp90 acts as a capacitor for evolution and buffers the effects of mutations, allowing their gradual accumulation (3, 4). When stress conditions overwhelm Hsp90, otherwise silent polymorphisms are expressed and can be selected if they provide a survival advantage. For example, Hsp90 potentiates the emergence of antifungal resistance and its inhibition reduces Candida albicans resistance to azoles and enhances action of caspofungin (CS) against Aspergilli (5, 6). These observations first implicated Hsp90 as a novel antifungal target and set the stage for Cowen et al. (2) to test synergistic effects of Hsp90 inhibitors and conventional antifungal drugs. In their study, Cowen et al. (2) tested several Hsp90 inhibitors combined with antifungal drugs of different mode of actions against evolutionarily divergent fungi in 2 complementary pathogenicity models. The Hsp90 inhibitors are geldanamycin (GdA) and analogs already in clinical trials as anticancer agents. 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) were tested in association with 2 commonly used antifungal drugs, fluconazole (FL; an ergosterol biosynthesis …

Dynamic duo takes down fungal villains