化学
抗菌剂
选择性
组合化学
生物化学
有机化学
催化作用
作者
Zhongxiang Wu,Ying Cai,Yajun Han,Yunhan Su,Tianyu Zhang,Xingyu Wang,Yan An,Liunan Wang,Sijing Wu,Wang Gan,Zhiye Zhang
标识
DOI:10.1021/acs.jmedchem.4c01855
摘要
The advancement of antimicrobial peptides (AMPs) as therapeutic agents is hindered by their poor selectivity. Recent evidence indicates that controlled disruption of the amphipathicity of α-helical AMPs may increase the selectivity. This study investigated the role of imperfect amphipathicity in optimizing AMPs with varied sequences to enhance their activity and selectivity. Among these, the lead peptide RI-18, characterized by an imperfectly amphipathic α-helical structure, demonstrated potent and broad-spectrum antibacterial activity without inducing hemolytic or cytotoxic effects. RI-18 effectively eliminated planktonic and biofilm-associated bacteria as well as persister cells and exhibited high bacterial plasma membrane affinity, inducing rapid membrane permeabilization and rupture. Notably, RI-18 significantly reduced bacterial loads without promoting bacterial resistance, highlighting its therapeutic potential. Overall, this study identified RI-18 as a promising antimicrobial candidate. The rational strategy of tuning imperfect amphipathicity to enhance the AMP activity and selectivity may facilitate the design and development of AMPs.
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