PDF(Pubmed)
Abstract：
Polymyxins are gram-negative antibiotics that target lipid A, the conserved membrane anchor of lipopolysaccharide in the outer membrane. Despite their clinical importance, the molecular mechanisms underpinning polymyxin activity remain unresolved. Here, we use surface plasmon resonance to kinetically interrogate interactions between polymyxins and lipid A and derive a phenomenological model. Our analyses suggest a lipid A-catalyzed, three-state mechanism for polymyxins: transient binding, membrane insertion, and super-stoichiometric cluster accumulation with a long residence time. Accumulation also occurs for brevicidine, another lipid A-targeting antibacterial molecule. Lipid A modifications that impart polymyxin resistance and a non-bactericidal polymyxin derivative exhibit binding that does not evolve into long-lived species. We propose that transient binding to lipid A permeabilizes the outer membrane and cluster accumulation enables the bactericidal activity of polymyxins. These findings could establish a blueprint for discovery of lipid A-targeting antibiotics and provide a generalizable approach to study interactions with the gram-negative outer membrane.
摘要：
多粘菌素是针对脂质A的革兰氏阴性抗生素，脂多糖在外膜中的保守膜锚。尽管它们在临床上很重要，支持多粘菌素活性的分子机制仍未解决。这里,我们使用表面等离子体共振来动力学询问多粘菌素和脂质A之间的相互作用，并得出现象学模型。我们的分析表明脂质A催化，多粘菌素的三态机制：瞬时结合，膜插入，和超化学计量团簇积累，停留时间长。布雷维定也会发生积累，另一种靶向脂质A的抗菌分子。脂质赋予多粘菌素抗性和非杀菌性多粘菌素衍生物的修饰表现出不进化为长寿命物种的结合。我们建议与脂质A的瞬时结合会透入外膜，簇的积累使多粘菌素具有杀菌活性。这些发现可以为发现靶向脂质A的抗生素建立蓝图，并为研究与革兰氏阴性外膜的相互作用提供可推广的方法。
