Bioinformatics Institute, A*STAR, 30 Biopolis street, Matrix, Singapore 138671.
Singapore Eye Research Institute, Singapore 169856, Singapore.
J Chem Inf Model. 2020 Oct 26;60(10):4975-4984. doi: 10.1021/acs.jcim.0c01051. Epub 2020 Oct 5.
Colistin or polymyxin B is the last resort antibiotic to treat infections of multidrug-resistant Gram-negative bacteria by disrupting their outer membranes. The recent emergence of Gram-negative bacteria that demonstrate colistin resistance, particularly plasmid-mediated mobile colistin resistance (), poses a big challenge to the treatment of multidrug resistance infections. Using molecular dynamics simulations, we explore the mechanism of colistin resistance in a model lipid A bilayer mimicking the Gram-negative -1 bacterial outer membrane. The simulation results reveal that the outer membrane of normal Gram-negative bacteria is stabilized by salt bridges between positively charged divalent ions and negatively charged phosphate groups of the membranes. In the presence of positively charged polymyxin B, these salt bridges are disrupted, and calcium is released into the aqueous phase, resulting in membrane disruption. In contrast, the lipid A in the outer membrane of -1 bacteria has a novel modification, this being a covalently attached phosphoethanolamine group. This group enables the formation of a large number of hydrogen bonds between the amine and phosphate groups, resulting in an electrostatic net on the membrane. This extensive noncovalent electrostatic cross-linking between the lipid molecules collectively enhances the membrane stability and results in resistance to the action of cationic peptides such as polymyxin B. The simulation results shed new atomistic insights for understanding the mechanistic basis of colistin resistance and provide clues for the design of new membrane disruptors and permeabilizers to treat -1 infections.
黏菌素或多黏菌素 B 是破坏其外膜来治疗多重耐药革兰氏阴性菌感染的最后手段抗生素。最近出现的具有黏菌素耐药性的革兰氏阴性菌，特别是质粒介导的移动性黏菌素耐药性 ()，对治疗多重耐药感染构成了巨大挑战。我们使用分子动力学模拟，探索了模拟革兰氏阴性菌外膜的模型脂质 A 双层中黏菌素耐药的机制。模拟结果表明，正常革兰氏阴性菌的外膜通过带正电荷的二价离子和膜上带负电荷的磷酸基团之间的盐桥稳定。在带正电荷的多黏菌素 B 的存在下，这些盐桥被破坏，钙离子释放到水相中，导致膜破裂。相比之下，-1 细菌外膜中的脂质 A 具有一种新的修饰，即共价连接的磷乙醇胺基团。该基团能够在胺和磷酸基团之间形成大量氢键，在膜上形成静电网络。脂质分子之间这种广泛的非共价静电交联共同增强了膜的稳定性，导致对阳离子肽（如多黏菌素 B）的作用产生耐药性。模拟结果为理解黏菌素耐药的机制基础提供了新的原子水平见解，并为设计新的膜破坏剂和通透性增强剂以治疗 -1 感染提供了线索。
