Rahman Md Ramim Tanver, Guay Louis-David, Fliss Ismail, Biron Eric
Faculty of Pharmacy, Université Laval, Québec, QC G1V 0A6, Canada.
Laboratory of Medicinal Chemistry, CHU de Québec-Université Laval Research Center, Québec, QC G1V 4G2, Canada.
Antibiotics (Basel). 2025 Apr 5;14(4):385. doi: 10.3390/antibiotics14040385.
The emergence of multidrug-resistant (MDR) presents a critical global health challenge due to treatment failures and high mortality rates. Faced with this growing threat, new antimicrobials with original modes of action are urgently needed, and antimicrobial peptides proved to be promising alternatives.
The aim of this study is to explore the structure-function relationship of the lipopeptide humimycin A, compare the spectrum of activity of the synthetic analogs against a panel of isolates, and investigate their binding to the humimycin target, the lipid II flippase MurJ.
Humimycin A and 15 analogs were produced by solid-phase peptide synthesis, and their antimicrobial activity was evaluated by agar diffusion and microtitration assays against 19 isolates from bovine mastitis and other pathogens.
Among the synthesized peptides, four humimycin analogs exhibited activity against methicillin-sensitive and methicillin-resistant , as well as several isolates in the panel, including MDR , with minimal inhibitory concentration values ranging from 0.5 to 256 µg/mL. Results from the structure-activity relationship study showed that the β-hydroxymyristoyl lipid chain and C-terminal carboxylic acid are essential for antimicrobial efficacy. In presence of human erythrocytes, the active humimycin analogs exhibited moderate hemolytic activity, suggesting selectivity indexes ranging from 3 to 27 against the more sensitive strains. Critical micelle concentration measurements elucidated micelle formation and proved to not be essential for the antibacterial activity. Molecular docking and 100 ns simulations with the lipid II flippase MurJ (PDB: 5T77) provided favorable binding energy.
The findings underscore the potential of humimycin analogs as antimicrobials for preventing and treating MDR infections in veterinary, animal husbandry, and human medicine.
多重耐药（MDR）的出现由于治疗失败和高死亡率而成为全球关键的健康挑战。面对这一日益严重的威胁，迫切需要具有全新作用模式的新型抗菌药物，而抗菌肽被证明是有前景的替代物。
本研究旨在探索脂肽腐霉素A的结构-功能关系，比较合成类似物对一组分离株的活性谱，并研究它们与腐霉素靶标——脂质II翻转酶MurJ的结合情况。
通过固相肽合成制备腐霉素A和15种类似物，并通过琼脂扩散法和微量滴定法评估它们对19株来自牛乳腺炎及其他病原体的分离株的抗菌活性。
在合成的肽中，四种腐霉素类似物对甲氧西林敏感和耐药的金黄色葡萄球菌以及该组中的几种分离株，包括多重耐药的金黄色葡萄球菌均表现出活性，最低抑菌浓度值范围为0.5至256μg/mL。构效关系研究结果表明，β-羟基肉豆蔻酰脂质链和C端羧酸对抗菌效力至关重要。在存在人红细胞的情况下，活性腐霉素类似物表现出中等程度的溶血活性，表明针对更敏感的金黄色葡萄球菌菌株的选择性指数范围为3至27。临界胶束浓度测量阐明了胶束的形成，并且证明其对抗菌活性并非必不可少。与脂质II翻转酶MurJ（PDB：5T77）进行的分子对接和100 ns模拟提供了有利的结合能。
这些发现强调了腐霉素类似物作为预防和治疗兽医、畜牧业及人类医学中多重耐药金黄色葡萄球菌感染的抗菌药物的潜力。
