Efficient Screening of High Bacterial Cell-Selective Antimicrobial Peptides via Proline Regulation Combined with a Universal Secondary Structure Template.

Authors

Pengyi Yan, Lanqing Hu, Bingqian Ren, Xueting Liu, Zufang Ba, Jie Liu, Zhongwei Yu, Qingyang Xu, Liru Yuan, Jieyu Lu, Yumeng Li, Xia Tang, Jiayu Sun, Chao Zhong, Yun Zhang, Hui Liu, Sanhu Gou, Jingman Ni

Published in

Journal of medicinal chemistry. Volume 69. Issue 17. Pages 20804-20826. Sep 10, 2026.

Abstract

To study the ″preference″ of bacterial membranes for the secondary structure of antimicrobial peptides (AMPs), we designed a universal palindromic sequence template G(LK)n(KL)nG-NH2 (designated as GnPm, where n = 2-6 and m = 0-3) that can cover various secondary structures of AMPs, with 0 to 3 proline residues uniformly and dispersedly inserted in the middle region to regulate their secondary structures. Results confirmed that both the numbers of LK/KL repeats and proline can regulate secondary structure, thereby controlling the antibacterial activity of the AMPs. The optimized peptide G5P2 exhibits potent antibacterial activity via a typical membrane-disrupting mechanism, is not prone to inducing bacterial drug resistance, can synergize with traditional antibiotics to delay the emergence of antibiotic resistance, and has excellent in vivo antibacterial activity (a 93.52% bacterial clearance) and high safety (LD50 = 89.87 mg/kg), thus providing new chemical strategies and candidate molecules for the clinical management of drug-resistant bacterial infections.

PMID:
42720485
Bibliographic data and abstract were imported from PubMed on 10 Sep 2026.

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