Key Laboratory of Structure-Based Drugs Design and Discovery (Ministry of Education), School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
J Med Chem. 2023 Sep 28;66(18):13247-13265. doi: 10.1021/acs.jmedchem.3c01254. Epub 2023 Sep 19.
The extensive use of antifungal drugs has resulted in severe drug resistance, making clinical treatment of fungal infections more difficult. Biofilm inhibitors can overcome drug resistance by inhibiting fungal biofilm formation. In this study, some coumarins with antibiofilm activity were merged into CYP51 inhibitors to produce novel molecules possessing potent antiresistance activity. As expected, most compounds exhibited excellent in vitro antifungal activity against pathogenic fungi, especially fluconazole-resistant candidiasis. Then, their mechanism was confirmed by sterol composition analysis and morphological observation. Biofilm inhibition and down-regulation of resistance-related genes were employed to confirm the compounds' antiresistance mechanisms. Significantly, compound demonstrated fungicidal activity against fluconazole-resistant . Most importantly, compound showed potent in vivo antifungal activity against pathogenic fungi and fluconazole-resistant strains. Preliminary pharmacokinetic and toxicity tests demonstrated that the compounds possessed favorable druggability. Taken together, compound represents a promising lead to develop novel antifungal agents for treating azole-resistant candidiasis.
抗真菌药物的广泛使用导致了严重的耐药性，使真菌感染的临床治疗更加困难。生物膜抑制剂可以通过抑制真菌生物膜的形成来克服耐药性。在这项研究中，一些具有抗生物膜活性的香豆素被合并到 CYP51 抑制剂中，产生了具有强大抗耐药性的新型分子。正如预期的那样，大多数化合物对致病性真菌表现出优异的体外抗真菌活性，特别是对氟康唑耐药的念珠菌。然后，通过甾醇组成分析和形态观察来证实它们的机制。通过抑制生物膜和下调耐药相关基因来证实化合物的抗耐药机制。值得注意的是，化合物 对氟康唑耐药的 表现出杀菌活性。最重要的是，化合物 对致病性真菌和氟康唑耐药株具有很强的体内抗真菌活性。初步的药代动力学和毒性试验表明，这些化合物具有良好的成药性。总之，化合物 代表了开发治疗唑类耐药性念珠菌病的新型抗真菌药物的有前途的先导化合物。
