Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
ACS Infect Dis. 2021 Jan 8;7(1):64-78. doi: 10.1021/acsinfecdis.0c00545. Epub 2020 Dec 9.
The development of antimicrobial compounds is now regarded as an urgent problem. Antimicrobial peptides (AMPs) have great potential to become novel antimicrobial drugs. Feleucin-K3 is an α-helical cationic AMP isolated from the skin secretion of the Asian bombinid toad species and has antimicrobial activity. In our previous studies, amino acid scanning of Feleucin-K3 was performed to determine the key site affecting its activity. In this study, we investigated and synthesized a series of analogues that have either a natural or an unnatural hydrophobic amino acid substitution at the fourth amino acid residue of Feleucin-K3. Among these analogues, Feleucin-K59 (K59), which has an α-(4-pentenyl)-Ala substitution, was shown to have increased antimicrobial activity against both standard and drug-resistant strains of clinical common bacteria, improved stability, no hemolytic activity at antimicrobial concentrations, and no resistance. In addition, K59 has potent antibiofilm activity . More importantly, K59 showed better antimicrobial and antibiofilm activities against drug-resistant bacteria in experiments in mice than traditional antibiotics. In this preliminary study of the mechanism of action, we found that K59 could rapidly kill bacteria by a dual-action mechanism of disrupting the cell membrane and binding to intracellular DNA, thus making it difficult for bacteria to develop resistance.
抗菌化合物的开发现在被认为是一个紧迫的问题。抗菌肽（AMPs）有很大的潜力成为新型抗菌药物。Feleucin-K3 是一种从亚洲雨蛙属物种的皮肤分泌物中分离出来的α-螺旋阳离子 AMP，具有抗菌活性。在我们之前的研究中，对 Feleucin-K3 进行了氨基酸扫描，以确定影响其活性的关键部位。在这项研究中，我们研究并合成了一系列类似物，这些类似物在 Feleucin-K3 的第四个氨基酸残基处具有天然或非天然疏水性氨基酸取代。在这些类似物中，具有α-(4-戊烯基)-Ala 取代的 Feleucin-K59（K59）显示出对标准和耐药临床常见细菌株的抗菌活性增强、稳定性提高、在抗菌浓度下无溶血活性且无耐药性。此外，K59 具有很强的抗生物膜活性。更重要的是，K59 在小鼠实验中对耐药菌的抗菌和抗生物膜活性均优于传统抗生素。在这项作用机制的初步研究中，我们发现 K59 可以通过破坏细胞膜和与细胞内 DNA 结合的双重作用机制快速杀死细菌，从而使细菌难以产生耐药性。
