Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, Yunnan 650031, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
J Med Chem. 2024 Nov 14;67(21):19561-19572. doi: 10.1021/acs.jmedchem.4c01855. Epub 2024 Nov 1.
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.
抗菌肽 (AMPs) 作为治疗剂的发展受到其选择性差的阻碍。最近的证据表明，控制 α-螺旋 AMP 的两亲性的破坏可能会增加选择性。本研究调查了不完美两亲性在优化具有不同序列的 AMP 以提高其活性和选择性中的作用。在这些 AMP 中，先导肽 RI-18 具有不完美的两亲性 α-螺旋结构，表现出强大且广谱的抗菌活性，同时不会引起溶血或细胞毒性作用。RI-18 可有效消除浮游和生物膜相关细菌以及持久细胞，并表现出对细菌质膜的高亲和力，导致快速的膜通透性和破裂。值得注意的是，RI-18 显著降低了细菌负荷而没有促进细菌耐药性，突出了其治疗潜力。总的来说，本研究确定 RI-18 是一种很有前途的抗菌候选物。通过调整不完美两亲性来增强 AMP 活性和选择性的合理策略可能有助于 AMP 的设计和开发。
