Ramaswamy Venkata Krishnan, Cacciotto Pierpaolo, Malloci Giuliano, Vargiu Attilio V, Ruggerone Paolo
Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy.
Department of Physics, University of Cagliari, Monserrato, Cagliari, Italy
Essays Biochem. 2017 Mar 3;61(1):141-156. doi: 10.1042/EBC20160065. Print 2017 Feb 28.
Antimicrobial resistance is based on the multifarious strategies that bacteria adopt to face antibiotic therapies, making it a key public health concern of our era. Among these strategies, efflux pumps (EPs) contribute significantly to increase the levels and profiles of resistance by expelling a broad range of unrelated compounds - buying time for the organisms to develop specific resistance. In Gram-negative bacteria, many of these chromosomally encoded transporters form multicomponent 'pumps' that span both inner and outer membranes and are driven energetically by a primary or secondary transporter component.One of the strategies to reinvigorate the efficacy of antimicrobials is by joint administration with EP inhibitors (EPI), which either block the substrate binding and/or hinder any of the transport-dependent steps of the pump. In this review, we provide an overview of multidrug-resistance EPs, their inhibition strategies and the relevant findings from the various computational simulation studies reported to date with respect to deciphering the mechanism of action of inhibitors with the purpose of improving their rational design.
抗菌耐药性基于细菌应对抗生素治疗所采用的多种策略，这使其成为我们这个时代关键的公共卫生问题。在这些策略中，外排泵（EPs）通过排出多种不相关化合物，显著提高了耐药水平和耐药谱——为微生物争取时间以产生特异性耐药。在革兰氏阴性菌中，许多这些染色体编码的转运蛋白形成跨内膜和外膜的多组分“泵”，并由初级或次级转运蛋白组分提供能量驱动。恢复抗菌药物疗效的策略之一是与外排泵抑制剂（EPI）联合使用，EPI可阻断底物结合和/或阻碍泵的任何依赖转运的步骤。在本综述中，我们概述了多药耐药外排泵、其抑制策略以及迄今为止报道的各种计算模拟研究的相关发现，这些研究旨在破译抑制剂的作用机制，以改进其合理设计。
