Antibiotic resistance represents a critical public health threat, with an increasing number of Gram-negative pathogens demonstrating resistance to a broad range of clinical drugs. A primary challenge in enhancing antibiotic efficacy is overcoming the robust barrier presented by the bacterial outer membrane. Our research addresses a longstanding question: What is the rate of antibiotic permeation across the outer membrane (OM) of Gram-negative bacteria? Utilizing molecular dynamics (MD) simulations, we assess the passive permeability profiles of four commercially available antibiotics─gentamicin, novobiocin, rifampicin, and tetracycline across an asymmetric atomistic model of the Escherichia coli (E. coli) OM, employing the inhomogeneous solubility-diffusion model. Our examination of the interactions between these drugs and their environmental context during OM permeation reveals that extended hydrogen bond formation and drug–cation interactions significantly hinder the energetics of passive permeation, notably affecting novobiocin. Our MD simulations corroborate well with experimental data and reveal new implications of solvation on drug permeability, overall advancing the possible use of computational prediction of membrane permeability in future antibiotic discovery.

中文翻译：

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阐明抗生素通过大肠杆菌外膜的渗透性：来自分子动力学的见解


抗生素耐药性是一个严重的公共卫生威胁，越来越多的革兰氏阴性病原体表现出对多种临床药物的耐药性。提高抗生素疗效的主要挑战是克服细菌外膜带来的强大屏障。我们的研究解决了一个长期存在的问题：革兰氏阴性菌外膜 （OM） 的抗生素渗透率是多少？利用分子动力学 （MD） 模拟，我们在大肠杆菌 （E. coli） OM 的不对称原子模型中评估了四种市售抗生素——庆大霉素、新生霉素、利福平和四环素的被动渗透性曲线，采用不均匀溶解度-扩散模型。我们对 OM 渗透过程中这些药物之间的相互作用及其环境背景的检查表明，延长的氢键形成和药物-阳离子相互作用显着阻碍了被动渗透的能量学，特别是影响了新生霉素。我们的 MD 模拟与实验数据很好地印证了，并揭示了溶剂化对药物通透性的新影响，总体上推进了膜通透性计算预测在未来抗生素发现中的可能使用。