College of Pharmaceutical Sciences, Medical Research Institute, Southwest University, Chongqing 400715, PR China.
Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States.
J Med Chem. 2022 Jun 9;65(11):8029-8039. doi: 10.1021/acs.jmedchem.2c00595. Epub 2022 May 30.
The emergence of drug-resistant fungal pathogens poses great threats to an increasing number of vulnerable populations worldwide, and the need for novel antifungal agents is imperative. In this work, a series of lipo-γ-AA peptides were synthesized and evaluated for their biological activities. One lead, MW, exhibited potent and broad-spectrum antifungal activity. In addition, MW potently boosted the efficacy of fluconazole against clinical azole-resistant isolates. Mechanistic investigation showed that the lead compound disrupted the cell membrane, significantly boosted the production of reactive oxygen species, and undermined the function of the efflux pump, thus resensitizing drug-resistant to fluconazole. Notably, coadministration of MW and fluconazole exhibited potent antifungal activity in a murine model of mucocutaneous candidiasis. Our results demonstrated that lipo-γ-AA peptides have great promise for use alone or in combination to combat drug-resistant infections.
耐药真菌病原体的出现对全球越来越多的弱势群体构成了巨大威胁，因此迫切需要新型抗真菌药物。在这项工作中，我们合成了一系列脂化γ-AA 肽，并评估了它们的生物学活性。一个先导化合物 MW 表现出强大而广谱的抗真菌活性。此外，MW 还能显著增强氟康唑对临床唑类耐药分离株的疗效。机制研究表明，该先导化合物破坏了细胞膜，显著增加了活性氧的产生，并破坏了外排泵的功能，从而使耐药真菌对氟康唑重新敏感。值得注意的是，MW 和氟康唑联合给药在黏膜皮肤念珠菌病的小鼠模型中表现出强大的抗真菌活性。我们的研究结果表明，脂化γ-AA 肽具有很大的应用潜力，可以单独使用或联合使用来对抗耐药真菌感染。
