Thursday, November 21, 2024
11/21/2024
Summary/Abstract Intrinsic and acquired drug resistance of pathogenic microorganisms poses a grave threat to human health and has enormous economic consequences worldwide. Fungal pathogens present a particular challenge because they are eukaryotes and share many of the same biological processes as the human hosts they infect. Among the most problematic fungal pathogens are species of Cryptococcus, which cause over 180,000 deaths per year across the globe. Cryptococcal meningitis, the major clinical manifestation of the disease, has a 100% mortality rate if left untreated. Even with best available therapies, mortality rates remain high because the number of drug classes that have distinct targets in fungi is very limited and the usefulness of current antifungal drugs is compromised by either dose-limiting host toxicity or the frequent emergence of high-grade resistance. New, non- cross-reactive targets for therapeutic intervention are urgently needed. In work performed with prior support from NIAID, we have shown that targeting the molecular chaperone Hsp90 in Cryptococcus and other fungi provides a powerful strategy to enhance the efficacy of antifungal drugs and abrogate drug resistance. The “druggability” of Hsp90 has been well established by many small molecules targeting this protein for the treatment of human cancers. The poor antifungal activity and toxicity of currently available drugs, however, demand development of fungal-selective inhibitors as proposed in this revised resubmission. To pursue the goal of fungal selectivity, our interdisciplinary team has now solved the structure of the drug- binding domain of Candida albicans and Cryptococcus neoformans Hsp90, both in unbound and inhibitor-bound states. These chemo-structural studies identified fungal-specific differences in conformational flexibility that allowed us to design, synthesize and characterize fungal-selective inhibitors of a new chemical class. Now, leveraging the new chemistry and structure-based design approaches we developed with previous funding, we will use our complementary expertise in fungal chemical and molecular biology (Cowen) and medicinal chemistry (Brown) to continue pursuing structure activity relationship (SAR) studies, but now augmented by newly developed computational algorithms to generate inhibitors with broad-spectrum antifungal activity. The efficacy of compounds alone and in combination with a standard antifungal will be tested in culture and in mice against drug-resistant C. albicans and C. neoformans. In addition to generating important basic insights, our results are likely to impact the treatment of invasive fungal infections in the near future by providing promising leads for development of actual antifungal drug candidates that operate in a new way.
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