Abstract
New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude their use as antifungals. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp90 from the most common human fungal pathogen, Candida albicans. Here we report structures for this NBD alone, in complex with ADP or in complex with known Hsp90 inhibitors. Encouraged by the conformational flexibility revealed by these structures, we synthesize an inhibitor with >25-fold binding-selectivity for fungal Hsp90 NBD. Comparing co-crystals occupied by this probe vs. anticancer Hsp90 inhibitors revealed major, previously unreported conformational rearrangements. These insights and our probe’s species-selectivity in culture support the feasibility of targeting Hsp90 as a promising antifungal strategy.
Highlights
New strategies are needed to counter the escalating threat posed by drug-resistant fungi
The N-terminal domain of C. albicans Hsp[90] shares the same architecture at the nucleotide-binding site, which interacts with both ADP and radicicol through hydrogen-bond interactions at the same amino acids (Asp[92] and Thr[174], Fig. 1c, middle and lower panels)
By fluorescence polarization (FP) assay, we found a moderate (1.4- to 4.6-fold) gain in fungal selectivity for several of our new oxime analogs in binding Hsp[90] in whole-cell extracts prepared from C. albicans (SC5314) compared to HEPG2, a human cancer cell line (Fig. 3b)
Summary
New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp[90] affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp[90] from the most common human fungal pathogen, Candida albicans. Comparing co-crystals occupied by this probe vs anticancer Hsp[90] inhibitors revealed major, previously unreported conformational rearrangements These insights and our probe’s species-selectivity in culture support the feasibility of targeting Hsp[90] as a promising antifungal strategy. Compromise of host Hsp[90] function with human homolog-optimized drugs (currently being tested in patients with cancer) comes with prohibitive side effects in the context of systemic fungal infections[7,16]. While fungal Hsp[90] serves as a promising therapeutic Achilles heel, the utility of targeting it depends on whether sufficient inhibitor selectivity can be achieved to avoid compromise of its human homolog[5,17]. Utilizing a variety of high affinity binding modes, these compounds all mimic the unusual conformation adopted by ATP upon binding within the chaperone’s nucleotide-binding domain (NBD) and inhibit ATP binding and hydrolysis, thereby blocking chaperone function[23]
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