Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research (SPER), Jamia Hamdard (Deemed to be University), New Delhi 110062, India.
CSIR-Institute of Genomics and Integrative Biology (IGIB), Sukhdev Vihar, Mathura Road, New Delhi 110025, India.
Bioorg Chem. 2024 Apr;145:107239. doi: 10.1016/j.bioorg.2024.107239. Epub 2024 Feb 24.
Antimicrobial resistance (AMR) is a serious global concern and a huge burden on the healthcare system. Antimicrobial peptides (AMPs) are considered as a solution of AMR due to their membrane-lytic and intracellular mode of action and therefore resistance development against AMPs is less frequent. One such AMPs, temporin-L (TL) is a 13-mer peptide reported as a potent and broad-spectrum antibacterial agent with significant immunomodulatory activity. However, TL is toxic to human erythrocytes at their antibacterial concentrations and therefore various analogues were synthesized with potent antimicrobial activity and lower hemolytic activity. In this work, we have selected a non-toxic engineered analogue of TL (eTL) and performed hydrocarbon stapling of amino acid residues at i to i + 4 positions at different part of sequence. The synthesized peptides were investigated against both the gram-positive and gram-negative bacteria as well as methicillin resistant S. aureus, its MIC was measured in the concentrations range of 0.9-15.2 µM. All analogues were found equal or better antibacterial as compared to parent peptide. Interestingly one analogue eTL [5-9] was found to be non-cytotoxic and stable in presence of the human serum. Mode of action studies revealed membrane depolarizing and disruptive mode of action with live MRSA. Further in vivo studies of antimicrobial against MRSA infection and anti-endotoxin activities in mice model revealed potential activity of the stapled peptide analogue. Overall, this reports on stapled analogue of the AMPs highlights an important strategy for the development of new antibacterial therapeutics against AMR.
抗微生物药物耐药性（AMR）是一个严重的全球问题，也是医疗保健系统的巨大负担。由于其膜溶解和细胞内作用模式，抗菌肽（AMPs）被认为是 AMR 的解决方案，因此 AMP 产生耐药性的情况较少。其中一种 AMP，即 temporin-L（TL），是一种 13 个氨基酸的肽，具有很强的抗菌活性和广谱抗菌活性，并且具有显著的免疫调节活性。然而，TL 在其抗菌浓度下对人红细胞有毒，因此合成了各种具有强大抗菌活性和较低溶血活性的类似物。在这项工作中，我们选择了一种无毒的 TL 工程类似物（eTL），并在序列的不同部位对 i 到 i+4 位的氨基酸残基进行了烃链 stapling。所合成的肽针对革兰氏阳性和革兰氏阴性细菌以及耐甲氧西林金黄色葡萄球菌（MRSA）进行了研究，其 MIC 测量范围在 0.9-15.2 μM 之间。所有类似物的抗菌活性均与亲本肽相当或更好。有趣的是，一种类似物 eTL [5-9] 被发现对人血清无细胞毒性且稳定。作用机制研究表明，该类似物与活 MRSA 具有膜去极化和破坏作用。进一步在 MRSA 感染的体内抗菌和抗内毒素活性研究中，发现了该 stapled 肽类似物的潜在活性。总的来说，本报告介绍了 AMP 的 stapled 类似物，突出了开发针对 AMR 的新型抗菌治疗方法的重要策略。
