Critical Role of Position 10 Residue in the Polymyxin Antimicrobial Activity.
Critical Role of Position 10 Residue in the Polymyxin Antimicrobial Activity.
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第10位残基在多粘菌素抗菌活性中的关键作用。
DOI：
10.1021/acs.jmedchem.2c01915
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发表时间：
2023-02
影响因子：
7.3
通讯作者：
N. Patil;Wendong Ma;Xukai Jiang;Xiao-shu He;Heidi H. Yu;Hasini Wickremasinghe;Jiping Wang;P. Thompson-P
中科院分区：
文献类型：
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作者：
N. Patil;Wendong Ma;Xukai Jiang;Xiao-shu He;Heidi H. Yu;Hasini Wickremasinghe;Jiping Wang;P. Thompson-P
多粘菌素（多粘菌素B和粘菌素）是脂肽类抗生素，用于治疗危及生命的多重耐药（MDR）革兰氏阴性细菌感染。不幸的是，它们的临床使用受到剂量限制性毒性和日益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粘菌素至关重要，尽管对多粘菌素核心支架中保守位置10苏氨酸（Thr）残基的作用知之甚少。在此，我们合成了30个在10位明确修饰的多粘菌素B1的新型类似物，研究了它们对革兰氏阴性菌的抗菌活性和体内毒性，并在细菌外膜上进行了分子动力学模拟。本研究首次揭示了β-羟基侧链在促进多粘菌素正确折叠构象中的立体化学要求和作用，从而驱动外膜渗透和抗菌活性。这些发现为开发更安全、更有效的新一代多粘菌素抗生素提供了重要信息。
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 B1 modified explicitly at position 10 and examined the antimicrobial activity against Gram-negative bacteria and in vivo 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.