Bonvin Etienne, Orsi Markus, Paschoud Thierry, Gopalasingam Ashvin, Reusser Jérémie, Köhler Thilo, van Delden Christian, Reymond Jean-Louis
Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, Bern, CH-3012, Switzerland.
Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, CH-1211, Switzerland.
Angew Chem Int Ed Engl. 2025 Jun 2;64(23):e202501299. doi: 10.1002/anie.202501299. Epub 2025 Apr 3.
Macrocycles have emerged as important new modalities in drug discovery. In the context of addressing the global threat of antimicrobial resistance, here we used a genetic algorithm as a computational tool to evolve peptide-peptoid macrocycles to resemble polymyxin B2 (PMB2), a macrocyclic lipopeptide natural product used as last resort antibiotic. Synthesis and testing of 41 PMB2 analogs revealed several peptide-peptoid macrocycles showing strong, although salt sensitive, activity against Escherichia coli and multidrug-resistant strains of Pseudomonas aeruginosa, high serum stability, and lower toxicity to kidney cells compared to PMB2. These macrocycles resembled PMB2 in terms of outer membrane permeabilization, inner membrane depolarization, lipopolysaccharide binding, and loss of activity when linearized, but, unlike PMB2, induced aggregation of intracellular contents, an effect was reported for other antimicrobial peptoids. These experiments exemplify a combined computational and experimental approach which might be generally useful to explore the chemical space of macrocyclic peptide natural products.
大环化合物已成为药物研发中的重要新形式。在应对全球抗生素耐药性威胁的背景下，我们在此使用遗传算法作为一种计算工具，来改造肽 - 类肽大环化合物，使其类似于多粘菌素B2（PMB2），一种用作最后手段抗生素的大环脂肽天然产物。对41种PMB2类似物的合成与测试表明，有几种肽 - 类肽大环化合物对大肠杆菌和多重耐药铜绿假单胞菌菌株表现出强活性（尽管对盐敏感）、高血清稳定性，并且与PMB2相比，对肾细胞的毒性更低。这些大环化合物在外膜通透化、内膜去极化、脂多糖结合以及线性化时活性丧失等方面与PMB2相似，但与PMB2不同的是，它们会诱导细胞内物质聚集，其他抗菌类肽也有这种效应的报道。这些实验例证了一种计算与实验相结合的方法，这可能普遍有助于探索大环肽天然产物的化学空间。
