School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore.
Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.
J Chem Inf Model. 2024 Nov 11;64(21):8310-8321. doi: 10.1021/acs.jcim.4c01249. Epub 2024 Oct 31.
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 () 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.
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对广泛的临床药物表现出耐药性。提高抗生素疗效的主要挑战是克服细菌外膜的强大屏障。我们的研究解决了一个长期存在的问题：抗生素穿过革兰氏阴性菌外膜 (OM) 的渗透率是多少？我们利用分子动力学 (MD) 模拟，通过非均匀溶解-扩散模型，评估了四种市售抗生素——庆大霉素、新生霉素、利福平、四环素在不对称原子模型的 () OM 中的被动渗透率分布。我们研究了这些药物在 OM 渗透过程中与环境相互作用，发现氢键的扩展和药物-阳离子相互作用极大地阻碍了被动渗透的能量学，特别是对新生霉素的影响。我们的 MD 模拟与实验数据吻合良好，并揭示了溶剂化对药物渗透性的新影响，总体上推进了计算预测在未来抗生素发现中的膜渗透性的可能应用。
