Understanding the selectivity in silico of colistin and daptomycin toward gram-negative and gram-positive bacteria, respectively, from the interaction with membrane phospholipids.

IF 3.9 Q2 MATHEMATICAL & COMPUTATIONAL BIOLOGY
Frontiers in bioinformatics Pub Date : 2025-07-17 eCollection Date: 2025-01-01 DOI:10.3389/fbinf.2025.1569480
Yesid Aristizabal, Yamil Liscano, José Oñate-Garzón
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Abstract

Antimicrobial resistance is a significant public health concern worldwide. Currently, infections by antibiotic-resistant Gram-negative and Gram-positive bacteria are managed using the lipopeptide antibiotics colistin and daptomycin, which target the microbial membrane. Despite the fact that both are short, cyclic, and have a common acylated group, they display remarkable antimicrobial selectivity. Colistin exhibits activity only against gram-negative bacteria, while daptomycin only against gram-positive bacteria. However, the mechanism behind this selectivity is unclear. Here, we performed molecular dynamics simulations to study the interactions between Escherichia coli membrane models composed of 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoethanolamine (POPE)/1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoglycerol (POPG) with daptomycin and colistin, independently. Similarly, we simulated the interaction between the Staphyloccocus aureus model membrane composed of POPG and cardiolipin (PMCL1) with both antibiotics. We observed that colistin interacted via hydrogen bonds and electrostatic interactions with the polar head of POPE in E. coli membrane models, mediated by 2,4-diaminobutyric acid (DAB) residues, which facilitated the insertion of its acyl tail into the hydrophobic core of the bilayer. In S. aureus membrane models, weaker interactions were observed with the polar head, particularly POPG, which was insufficient for the insertion of the lipid tail into the membrane. However, daptomycin displayed strong interactions with several POPG functional groups of the S. aureus membrane model, which favored the insertion of the fatty acid tail into the bilayer. Contrastingly, daptomycin showed negligible interactions with the E. coli membrane, except for the amino group of the POPE polar head, which might repel the calcium ions conjugated with the lipopeptide. Based on these results, we identified key amino acid-phospholipid interactions that likely contribute to this antibacterial selectivity, which might contribute to designing and developing future antimicrobial peptides.

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通过与膜磷脂的相互作用,了解粘菌素和达托霉素对革兰氏阴性和革兰氏阳性细菌的选择性。
抗菌素耐药性是世界范围内的一个重大公共卫生问题。目前,耐药革兰氏阴性和革兰氏阳性细菌的感染是使用针对微生物膜的脂肽抗生素粘菌素和达托霉素来控制的。尽管事实上两者都是短的,环状的,并且有一个共同的酰化基团,但它们表现出显著的抗菌选择性。粘菌素仅对革兰氏阴性菌有活性,而达托霉素仅对革兰氏阳性菌有活性。然而,这种选择性背后的机制尚不清楚。在这里,我们进行了分子动力学模拟,研究了由1-棕榈酰基-2-油基- n-甘油-3-磷酸乙醇胺(POPE)/1-棕榈酰基-2-油基- n-甘油-3-磷酸甘油(POPG)组成的大肠杆菌膜模型与达托霉素和粘菌素的相互作用。同样,我们模拟了由POPG和心磷脂(PMCL1)组成的金黄色葡萄球菌模型膜与这两种抗生素的相互作用。我们观察到粘菌素在大肠杆菌膜模型中通过氢键和静电相互作用与POPE的极性头相互作用,由2,4-二氨基丁酸(DAB)残基介导,这有助于其酰基尾部插入双层膜的疏水核心。在金黄色葡萄球菌膜模型中,观察到与极性头的相互作用较弱,特别是与POPG的相互作用,不足以将脂质尾部插入膜中。然而,达托霉素与金黄色葡萄球菌膜模型的几个POPG功能基团表现出强烈的相互作用,这有利于脂肪酸尾部插入双分子层。相比之下,达托霉素与大肠杆菌膜的相互作用可以忽略不计,除了POPE极性头的氨基可能排斥与脂肽结合的钙离子。基于这些结果,我们确定了可能有助于这种抗菌选择性的关键氨基酸-磷脂相互作用,这可能有助于设计和开发未来的抗菌肽。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
2.60
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