Azole-triphenylphosphonium conjugates combat antifungal resistance and alleviate the development of drug-resistance
Azole-triphenylphosphonium conjugates combat antifungal resistance and alleviate the development of drug-resistance
复制标题
唑-三苯基鏻缀合物可对抗抗真菌耐药性并减轻耐药性的发展
DOI：
10.1016/j.bioorg.2021.104771
复制
发表时间：
2021-03-11
影响因子：
5.1
通讯作者：
Lou, Hongxiang
中科院分区：
文献类型：
--
作者：
Wang, Xin;Liu, Jun;Lou, Hongxiang
唑类抗真菌药常用于治疗真菌感染，但已导致耐药性的发生。因此，开发唑类衍生物（AZDs），既可以打击已建立的耐药真菌菌株和逃避耐药性是非常重要的。在这项研究中，我们合成了一系列的AZDs与氟康唑（FLC）的骨架共轭与靶向三苯基膦阳离子（TPP+）。这些AZD对唑类敏感和唑类耐药念珠菌菌株均表现出较强的抗菌活性，但未引起明显的耐药性。此外，两种代表性的AZD，20和25，与Hsp90抑制剂对C.对FLC和Hsp90抑制剂的组合治疗具有抗性的白色念珠菌菌株。AZD 25细胞毒性极低，对C.白色念珠菌生物膜形成。机制研究表明，AZD 25抑制真菌膜组分麦角固醇的生物合成，并干扰线粒体功能。我们的研究结果提供了一种解决真菌耐药性问题的替代方法。
Azole antifungals are commonly used to treat fungal infections but have resulted in the occurrence of drug resistance. Therefore, developing azole derivatives (AZDs) that can both combat established drug-resistant fungal strains and evade drug resistance is of great importance. In this study, we synthesized a series of AZDs with a fluconazole (FLC) skeleton conjugated with a mitochondria-targeting triphenylphosphonium cation (TPP+). These AZDs displayed potent activity against both azole-sensitive and azole-resistant Candida strains without eliciting obvious resistance. Moreover, two representative AZDs, 20 and 25, exerted synergistic antifungal activity with Hsp90 inhibitors against C. albicans strains resistant to the combination treatment of FLC and Hsp90 inhibitors. AZD 25, which had minimal cytotoxicity, was effective in preventing C. albicans biofilm formation. Mechanistic investigation revealed that AZD 25 inhibited the biosynthesis of the fungal membrane component ergosterol and interfered with mitochondrial function. Our findings provide an alternative approach to address fungal resistance problems.