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Progress and prospects for targeting Hsp90 to treat fungal infections

机译：Hsp90靶向治疗真菌感染的研究进展与前景

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Summary Fungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.
机译：小结真菌病原体对全球人类健康构成重大威胁。他们每年感染数十亿人，导致至少1·500万人死亡。由于临床上有用的抗真菌药物数量有限，并且出现了耐药性，因此难以治疗真菌感染。增强抗真菌药功效并阻止耐药性演变的一种有希望的新策略是靶向分子伴侣Hsp90。作为抗癌药正在开发的Hsp90功能的药理学抑制剂有可能被重新用作某些应用（例如生物膜感染）的联合抗真菌治疗的药物。但是，对于全身感染，有效的联合治疗方案可能需要能够选择性靶向病原体中Hsp90的Hsp90抑制剂，或者需要采取其他策略来破坏Hsp90伴侣机的功能。原则上，可以通过靶向Hsp90伴侣蛋白或Hsp90功能的调节剂（在病原体和宿主之间比Hsp90更具差异性）来选择性破坏病原体中的Hsp90功能。抗真菌联合疗法还可以利用Hsp90的下游效应子，这些效应子对真菌的耐药性和毒力至关重要。在这里，我们讨论建立Hsp90作为威胁生命的真菌感染的重要治疗目标的进展和前景。

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