Aix-Marseille Univ, INSERM, SSA, MCT, Marseille, France.
Centre de Biophysique Moléculaire, CNRS, UPR 4301, Orléans, France.
Commun Biol. 2024 Nov 14;7(1):1508. doi: 10.1038/s42003-024-07168-4.
The sophisticated envelope of Gram-negative bacteria modulates the uptake of small molecules in a side-chain-sensitive manner. Despite intensive theoretical and experimental investigations, a general set of pathways underpinning antibiotic uptake has not been identified. This manuscript discusses the passive influx versus active efflux of antibiotics, considering the responsible membrane proteins and the transported molecules. Recent methods have analyzed drug transport across the bacterial membrane in order to understand their activity. The combination of in vitro, in cellulo and in silico methods shed light on the key, mainly electrostatic, interactions between the molecule surface, porins and transporters during permeation. A key factor is the relationship between the dose of an active compound near its target and its antibacterial activity during the critical early window. Today, methodology breakthroughs provide fruitful tools to precisely dissect drug transport, identify key steps in drug resistance associated with membrane impermeability and efflux, and highlight key parameters to generate more effective drugs.
革兰氏阴性菌复杂的外膜以侧链敏感的方式调节小分子的摄取。尽管进行了深入的理论和实验研究，但尚未确定一组普遍的抗生素摄取途径。本文讨论了抗生素的被动流入与主动流出，同时考虑了负责的膜蛋白和被转运的分子。最近的方法分析了抗生素在细菌膜中的跨膜运输，以了解其活性。体外、细胞内和计算机模拟方法的结合揭示了在渗透过程中分子表面、孔蛋白和转运体之间的主要静电相互作用。一个关键因素是活性化合物在其靶标附近的剂量与其在关键早期窗口期间的抗菌活性之间的关系。如今，方法学的突破为精确剖析药物转运、识别与膜通透性和外排相关的耐药性中的关键步骤，以及突出生成更有效药物的关键参数提供了富有成效的工具。
