Department of Physics, University of Cagliari, s.p. 8, Cittadella Universitaria, 09042 Monserrato, CA, Italy.
Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A., Piazzale della stazione snc, 00071 S. Palomba-Pomezia, Rome, Italy.
Biochim Biophys Acta Biomembr. 2019 Jul 1;1861(7):1397-1408. doi: 10.1016/j.bbamem.2019.05.004. Epub 2019 May 8.
The drug/proton antiporter AcrB, which is part of the major efflux pump AcrABZ-TolC in Escherichia coli, is the paradigm transporter of the resistance-nodulation-cell division (RND) superfamily. Despite the impressive ability of AcrB to transport many chemically unrelated compounds, only a few of these ligands have been co-crystallized with the protein. Therefore, the molecular features that distinguish good substrates of the pump from poor ones have remained poorly understood to date. In this work, a thorough in silico protocol was employed to study the interactions of a series of congeneric compounds with AcrB to examine how subtle chemical differences affect the recognition and transport of substrates by this protein. Our analysis allowed us to discriminate among different compounds, mainly in terms of specific interactions with diverse sub-sites within the large distal pocket of AcrB. Our findings could provide valuable information for the design of new antibiotics that can evade the antimicrobial resistance mediated by efflux pump machinery.
药物/质子反转运蛋白 AcrB 是大肠杆菌主要外排泵 AcrABZ-TolC 的一部分，它是耐药性结节细胞分裂（RND）超家族的典型转运蛋白。尽管 AcrB 具有运输许多化学上无关的化合物的令人印象深刻的能力，但只有少数这些配体已与该蛋白共结晶。因此，迄今为止，泵的良好底物与不良底物之间的分子特征仍知之甚少。在这项工作中，我们采用了一种彻底的计算方法来研究一系列同系物化合物与 AcrB 的相互作用，以研究细微的化学差异如何影响该蛋白对底物的识别和运输。我们的分析使我们能够区分不同的化合物，主要是根据它们与 AcrB 大远端口袋内不同亚基的特定相互作用。我们的发现可以为设计能够逃避外排泵机制介导的抗菌药物耐药性的新型抗生素提供有价值的信息。
