Polymyxin B-inspired non-hemolytic tyrocidine A analogues with significantly enhanced activity against gram-negative bacteria: How cationicity impacts cell specificity and antibacterial mechanism.
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| Abstract |
Naturally occurring cyclic antimicrobial peptides (AMPs) such as tyrocidine A (Tyrc A) and gramicidin S (GS) are appealing targets for the development of novel antibiotics. However, their therapeutic potentials are limited by undesired hemolytic activity and relatively poor activity against Gram-negative bacteria. Inspired by polycationic lipopeptide polymyxin B (PMB), the so called 'last-resort' antibiotic for the treatment of infections caused by multidrug-resistant Gram-negative bacteria, we synthesized and biologically evaluated a series of polycationic analogues derived from Tyrc A. We were able to obtain peptide 8 that possesses 5 positive charges exhibiting potent activities against both Gram-negative and Gram-positive bacteria along with totally diminished hemolytic activity. Intriguingly, antibacterial mechanism studies revealed that, rather than the 'pore forming' model that possessed by Tyrc A, peptide 8 likely diffuses membrane in a 'detergent-like' manner. Furthermore, when treating mice with peritonitis-sepsis, peptide 8 showed excellent antibacterial and anti-inflammatory activities in vivo.
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| Authors | Jibao Zhu, Chengfei Hu, Zizhen Zeng, Xiaoyu Deng, Lingbing Zeng, Saisai Xie, Yuanying Fang, Yi Jin, Valérie Alezra, Yang Wan |
| Journal | European journal of medicinal chemistry (Eur J Med Chem) Vol. 221 Pg. 113488 (Oct 05 2021) ISSN: 1768-3254 [Electronic] France |
| PMID | 33991963 (Publication Type: Journal Article) |
| Copyright | Copyright © 2021 Elsevier Masson SAS. All rights reserved. |
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