Biomedicine Discovery Institute, Infection & Immunity Program and Department of Microbiology, Monash University, Clayton, Victoria 3800, Australia.
National Glycoengineering Research Center, Shandong University, Qingdao 266237, China.
J Med Chem. 2023 Feb 23;66(4):2865-2876. doi: 10.1021/acs.jmedchem.2c01915. Epub 2023 Feb 6.
Polymyxins (polymyxin B and colistin) are lipopeptide antibiotics used as a last-line treatment for life-threatening multidrug-resistant (MDR) Gram-negative bacterial infections. Unfortunately, their clinical use has been affected by dose-limiting toxicity and increasing resistance. Structure-activity (SAR) and structure-toxicity (STR) relationships are paramount for the development of safer polymyxins, albeit very little is known about the role of the conserved position 10 threonine (Thr) residue in the polymyxin core scaffold. Here, we synthesized 30 novel analogues of polymyxin B modified explicitly at position 10 and examined the antimicrobial activity against Gram-negative bacteria and toxicity and performed molecular dynamics simulations with bacterial outer membranes. For the first time, this study revealed the stereochemical requirements and role of the β-hydroxy side chain in promoting the correctly folded conformation of the polymyxin that drives outer membrane penetration and antibacterial activity. These findings provide essential information for developing safer and more efficacious new-generation polymyxin antibiotics.
多黏菌素（多黏菌素 B 和黏菌素）是一种脂肽类抗生素，可用作治疗危及生命的多重耐药（MDR）革兰氏阴性细菌感染的最后手段。不幸的是，其临床应用受到了剂量限制毒性和不断增加的耐药性的影响。结构-活性（SAR）和结构-毒性（STR）关系对于开发更安全的多黏菌素至关重要，但对于多黏菌素核心支架中保守的 10 位苏氨酸（Thr）残基的作用知之甚少。在这里，我们合成了 30 种新型多黏菌素 B 类似物，明确修饰了 10 位，并研究了它们对革兰氏阴性细菌的抗菌活性和毒性，并进行了与细菌外膜的分子动力学模拟。这项研究首次揭示了β-羟基侧链在促进多黏菌素正确折叠构象中的立体化学要求和作用，这种构象驱动了多黏菌素穿过外膜并发挥抗菌活性。这些发现为开发更安全、更有效的新一代多黏菌素抗生素提供了重要信息。
