Development of Lipo-γ-AA Peptides as Potent Antifungal Agents.
Development of Lipo-γ-AA Peptides as Potent Antifungal Agents.
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DOI：
10.1021/acs.jmedchem.2c00595
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发表时间：
2022-05
影响因子：
7.3
通讯作者：
Xing-Xing Zhang-Xing;Minghui Wang;Xiaodi Zhu;Yan-Jun Peng;Tiwei Fu;Chang-Hua Hu;Jianfeng Cai;G. Liao
中科院分区：
文献类型：
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作者：
Xing-Xing Zhang-Xing;Minghui Wang;Xiaodi Zhu;Yan-Jun Peng;Tiwei Fu;Chang-Hua Hu;Jianfeng Cai;G. Liao
耐药真菌病原体的出现对全球越来越多的脆弱人群构成了巨大威胁，对新型抗真菌药物的需求势在必行。本工作合成了一系列脂溶性γ-AA肽，并对其生物活性进行了评价。一个铅，MW 5，表现出强大的和广谱的抗真菌活性。此外，MW 5有效地提高了氟康唑对临床唑类耐药念珠菌分离株的疗效。机制研究表明，先导化合物破坏细胞膜，显着增加活性氧的产生，并破坏外排泵的功能，从而使耐药的白色念珠菌对氟康唑重新敏感。值得注意的是，MW 5和氟康唑联合给药在皮肤粘膜念珠菌病小鼠模型中表现出有效的体内抗真菌活性。我们的研究结果表明，脂-γ-AA肽有很大的希望单独使用或组合使用，以打击耐药念珠菌感染。
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, MW5, exhibited potent and broad-spectrum antifungal activity. In addition, MW5 potently boosted the efficacy of fluconazole against clinical azole-resistant Candida 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 Candida albicans to fluconazole. Notably, coadministration of MW5 and fluconazole exhibited potent in vivo 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 Candida infections.