Opperman Timothy J, Nguyen Son T
Microbiotix, Inc., Worcester, MA USA.
Front Microbiol. 2015 May 5;6:421. doi: 10.3389/fmicb.2015.00421. eCollection 2015.
Multidrug resistance (MDR) in Gram-negative pathogens, such as the Enterobacteriaceae and Pseudomonas aeruginosa, poses a significant threat to our ability to effectively treat infections caused by these organisms. A major component in the development of the MDR phenotype in Gram-negative bacteria is overexpression of Resistance-Nodulation-Division (RND)-type efflux pumps, which actively pump antibacterial agents and biocides from the periplasm to the outside of the cell. Consequently, bacterial efflux pumps are an important target for developing novel antibacterial treatments. Potent efflux pump inhibitors (EPIs) could be used as adjunctive therapies that would increase the potency of existing antibiotics and decrease the emergence of MDR bacteria. Several potent inhibitors of RND-type efflux pump have been reported in the literature, and at least three of these EPI series were optimized in a pre-clinical development program. However, none of these compounds have been tested in the clinic. One of the major hurdles to the development of EPIs has been the lack of biochemical, computational, and structural methods that could be used to guide rational drug design. Here, we review recent reports that have advanced our understanding of the mechanism of action of several potent EPIs against RND-type pumps.
革兰氏阴性病原体（如肠杆菌科细菌和铜绿假单胞菌）中的多重耐药性（MDR）对我们有效治疗由这些微生物引起的感染的能力构成了重大威胁。革兰氏阴性细菌中MDR表型发展的一个主要因素是耐药-固氮-分裂（RND）型外排泵的过表达，该泵可将抗菌剂和杀菌剂从周质主动泵出细胞外。因此，细菌外排泵是开发新型抗菌治疗方法的重要靶点。强效外排泵抑制剂（EPI）可作为辅助疗法，提高现有抗生素的效力，并减少MDR细菌的出现。文献中报道了几种强效的RND型外排泵抑制剂，其中至少有三个EPI系列在临床前开发项目中得到了优化。然而，这些化合物均未在临床上进行过测试。EPI开发的主要障碍之一是缺乏可用于指导合理药物设计的生化、计算和结构方法。在此，我们综述了最近的一些报告，这些报告加深了我们对几种强效EPI针对RND型泵的作用机制的理解。
