College of Biological Engineering, Henan University of Technology, 450001 Zhengzhou, Henan, PR China; Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou, Henan University of Technology, 450001 Zhengzhou, Henan, PR China.
College of Biological Engineering, Henan University of Technology, 450001 Zhengzhou, Henan, PR China; Key Laboratory of Functional Molecules for Biomedical Research, Zhengzhou, Henan University of Technology, 450001 Zhengzhou, Henan, PR China.
Biochem Pharmacol. 2023 May;211:115535. doi: 10.1016/j.bcp.2023.115535. Epub 2023 Apr 3.
High-efficiency and low-toxic antimicrobial peptides (AMPs) are supposed to be the future candidates to solve the increasingly prominent problems of Candida albicans infection and drug resistance. Generally, introduction of hydrophobic moieties on AMPs resulted in analogues with remarkably increased activity against pathogens. CGA-N9, an antifungal peptide found in our lab, is a Candida-selective antimicrobial peptide capable of preferentially killing Candida spp. relative to benign microorganisms with low toxicities. We speculate that fatty acid modification could improve the anti-Candida activity of CGA-N9. In the present investigation, a set of CGA-N9 analogues with fatty acid conjugations at N-terminus were obtained. The biological activities of CGA-N9 analogues were determined. The results showed that the n-octanoic acid conjugation of CGA-N9 (CGA-N9-C8) was the optimal CGA-N9 analogue with the highest anti-Candida activity and biosafety; exhibited the strongest biofilm inhibition activity and biofilm eradication ability; and the highest stability against protease hydrolysis in serum. Furthermore, CGA-N9-C8 is less prone to develop resistance for C. albicans in reference with fluconazole; CGA-N9-C8 also exhibited Candidacidal activity to the planktonic cells and the persister cells of C. albicans; reduced C. albicans susceptibility in a systemic candidiasis mouse model. In conclusion, fatty acid modification is an effective method to enhance the antimicrobial activity of CGA-N9, and CGA-N9-C8 is a promising candidate to defend C. albicans infection and resolve C. albicans drug resistance.
高效低毒的抗菌肽（AMPs）有望成为解决白色念珠菌感染和耐药性日益突出问题的未来候选药物。通常，在 AMPs 上引入疏水性部分会导致对病原体活性显著增加的类似物。CGA-N9 是我们实验室发现的一种抗真菌肽，是一种对念珠菌具有选择性的抗菌肽，能够优先杀死念珠菌属，而对良性微生物的毒性较低。我们推测脂肪酸修饰可以提高 CGA-N9 的抗白色念珠菌活性。在本研究中，获得了一组在 N 端带有脂肪酸结合的 CGA-N9 类似物。测定了 CGA-N9 类似物的生物学活性。结果表明，CGA-N9 的正辛酸结合物（CGA-N9-C8）是具有最高抗白色念珠菌活性和生物安全性的最佳 CGA-N9 类似物；表现出最强的生物膜抑制活性和生物膜清除能力；以及在血清中对蛋白酶水解的最高稳定性。此外，与氟康唑相比，CGA-N9-C8 不易使白色念珠菌产生耐药性；CGA-N9-C8 还对白色念珠菌浮游细胞和持久细胞具有杀菌活性；降低了系统性念珠菌病小鼠模型中白色念珠菌的易感性。总之，脂肪酸修饰是增强 CGA-N9 抗菌活性的有效方法，CGA-N9-C8 是一种有前途的候选药物，可以防御白色念珠菌感染并解决白色念珠菌耐药性问题。
