Recent advances toward a molecular mechanism of efflux pump inhibition.
Recent advances toward a molecular mechanism of efflux pump inhibition.
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DOI：
10.3389/fmicb.2015.00421
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发表时间：
2015
影响因子：
5.2
通讯作者：
Nguyen ST
中科院分区：
文献类型：
--
作者：
Opperman TJ;Nguyen ST
革兰氏阴性病原体（如肠杆菌科和铜绿假单胞菌）的多药耐药性（MDR）对我们有效治疗这些微生物引起的感染的能力构成了重大威胁。革兰氏阴性菌中MDR表型发展的主要成分是耐药-结瘤-分裂（RND）型外排泵的过表达，其主动将抗菌剂和杀生物剂从周质泵送到细胞外部。因此，细菌外排泵是开发新型抗菌治疗的重要目标。有效的外排泵抑制剂（EPIs）可以作为预防性治疗，增加现有抗生素的效力，减少MDR细菌的出现。在文献中已经报道了几种有效的RND型外排泵抑制剂，并且这些EPI系列中至少有三种在临床前开发计划中进行了优化。然而，这些化合物都没有在临床上进行过测试。EPI发展的主要障碍之一是缺乏可用于指导合理药物设计的生物化学、计算和结构方法。在这里，我们回顾了最近的报告，已经推进了我们的几个有效的EPI对RND型泵的作用机制的理解。
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.
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影响因子：
3.7
作者：
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通讯作者：
Burrows LL
影响因子：
3.2
作者：
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