Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
Eur J Med Chem. 2022 Jan 5;227:113961. doi: 10.1016/j.ejmech.2021.113961. Epub 2021 Oct 29.
Clinical treatment of candidiasis has suffered from increasingly severe drug resistance and limited efficacy. Thus, novel strategies to deal with drug resistance are highly desired to develop effective therapeutic agents. Herein, dual inhibition of heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) was validated as a new strategy to potentiate efficacy of fluconazole against resistant Candida albicans infections. The first generation of Hsp90/HDAC dual inhibitors were designed as synergistic enhancers to treat azoles-resistant candidiasis. In particular, compound J5 exhibited fungal-selective inhibitory effects on Hsp90 and HDACs, leading to low toxicity and excellent in vitro (FICI = 0.266) and in vivo synergistic antifungal potency to treat fluconazole resistant candidiasis. Antifungal-mechanistic investigation revealed that compound J5 suppressed important virulence factors and down-regulated expression of resistance-associated genes. Therefore, Hsp90/HDAC dual inhibitors represent a new strategy for the development of novel antifungal therapeutics to combat azole-resistant candidiasis.
临床治疗念珠菌病一直受到耐药性日益严重和疗效有限的困扰。因此，非常需要寻找新的策略来应对耐药性，以开发有效的治疗药物。本文验证了双重抑制热休克蛋白 90（Hsp90）和组蛋白去乙酰化酶（HDAC）作为增强氟康唑治疗耐药性白色念珠菌感染疗效的新策略。第一代 Hsp90/HDAC 双重抑制剂被设计为协同增强剂，以治疗唑类耐药性念珠菌病。特别是化合物 J5 对 Hsp90 和 HDACs 具有真菌选择性抑制作用，导致低毒性和优异的体外（FICI = 0.266）和体内协同抗真菌活性，可治疗氟康唑耐药性念珠菌病。抗真菌机制研究表明，化合物 J5 抑制了重要的毒力因子，并下调了耐药相关基因的表达。因此，Hsp90/HDAC 双重抑制剂为开发新型抗真菌治疗药物以对抗唑类耐药性念珠菌病提供了一种新策略。
