Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease Export

@article{citeulike:4132206, abstract = {10.1073/pnas.0813394106 Invasive fungal infections are a leading cause of mortality among immunocompromised individuals. Treatment is notoriously difficult with the limited armamentarium of antifungal drugs, whose efficacy is compromised by host toxicity, a limited activity spectrum, or the emergence of drug resistance. We previously established that the molecular chaperone Hsp90 enables the emergence and maintenance of fungal drug resistance. For the most prevalent fungal pathogen of humans, , Hsp90 mediates resistance to azoles, which inhibit ergosterol biosynthesis and are the most widely deployed antifungals in the clinic. For the emerging opportunistic pathogen , Hsp90 is required for basal resistance to echinocandins, which inhibit β(1, 3)-glucan synthesis and are the only new class of antifungals to reach the clinic in decades. Here, we explore the therapeutic potential of Hsp90 inhibitors in fungal disease using a tractable host-model system, larvae of the greater wax moth , and a murine model of disseminated disease. Combination therapy with Hsp90 inhibitors that are well tolerated in humans and an azole rescued larvae from lethal infections. Combination therapy with an Hsp90 inhibitor and an echinocandin rescued larvae from infections with the most lethal mold, . In a murine model of disseminated candidiasis, genetic compromise of expression enhanced the therapeutic efficacy of an azole. Thus, harnessing Hsp90 provides a much-needed strategy for improving the treatment of fungal disease because it enhances the efficacy of existing antifungals, blocks the emergence of drug resistance, and exerts broad-spectrum activity against diverse fungal pathogens.}, author = {Cowen, Leah E. and Singh, Sheena D. and K\"{o}hler, Julia R. and Collins, Cathy and Zaas, Aimee K. and Schell, Wiley A. and Aziz, Hamza and Mylonakis, Eleftherios and Perfect, John R. and Whitesell, Luke and Lindquist, Susan}, citeulike-article-id = {4132206}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0813394106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/8/2818.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/8/2818.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19196973}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19196973}, day = {24}, doi = {10.1073/pnas.0813394106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {anti-fungal}, month = {February}, number = {8}, pages = {2818--2823}, posted-at = {2009-03-04 16:02:53}, priority = {2}, title = {Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease}, url = {http://dx.doi.org/10.1073/pnas.0813394106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:4132206 L3 - citeulike-article-id:4132206 N2 - 10.1073/pnas.0813394106 Invasive fungal infections are a leading cause of mortality among immunocompromised individuals. Treatment is notoriously difficult with the limited armamentarium of antifungal drugs, whose efficacy is compromised by host toxicity, a limited activity spectrum, or the emergence of drug resistance. We previously established that the molecular chaperone Hsp90 enables the emergence and maintenance of fungal drug resistance. For the most prevalent fungal pathogen of humans, , Hsp90 mediates resistance to azoles, which inhibit ergosterol biosynthesis and are the most widely deployed antifungals in the clinic. For the emerging opportunistic pathogen , Hsp90 is required for basal resistance to echinocandins, which inhibit β(1, 3)-glucan synthesis and are the only new class of antifungals to reach the clinic in decades. Here, we explore the therapeutic potential of Hsp90 inhibitors in fungal disease using a tractable host-model system, larvae of the greater wax moth , and a murine model of disseminated disease. Combination therapy with Hsp90 inhibitors that are well tolerated in humans and an azole rescued larvae from lethal infections. Combination therapy with an Hsp90 inhibitor and an echinocandin rescued larvae from infections with the most lethal mold, . In a murine model of disseminated candidiasis, genetic compromise of expression enhanced the therapeutic efficacy of an azole. Thus, harnessing Hsp90 provides a much-needed strategy for improving the treatment of fungal disease because it enhances the efficacy of existing antifungals, blocks the emergence of drug resistance, and exerts broad-spectrum activity against diverse fungal pathogens. IS - 8 JF - Proceedings of the National Academy of Sciences EP - 2823 TI - Harnessing Hsp90 function as a powerful, broadly effective therapeutic strategy for fungal infectious disease VL - 106 SP - 2818 KW - anti-fungal AU - Cowen, Leah AU - Singh, Sheena AU - Köhler, Julia AU - Collins, Cathy AU - Zaas, Aimee AU - Schell, Wiley AU - Aziz, Hamza AU - Mylonakis, Eleftherios AU - Perfect, John AU - Whitesell, Luke AU - Lindquist, Susan PY - 2009/02/24/ UR - http://dx.doi.org/10.1073/pnas.0813394106 ER -