Antibiotic efflux pumps in Gram-negative bacteria:: the inhibitor response strategy
Antibiotic efflux pumps in Gram-negative bacteria:: the inhibitor response strategy
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DOI：
10.1093/jac/dkl493
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发表时间：
2007-06-01
影响因子：
5.2
通讯作者：
Pages, Jean-Marie
中科院分区：
文献类型：
--
作者：
Mahamoud, Abdallah;Chevalier, Jacqueline;Pages, Jean-Marie
经过几十年持续成功的抗生素治疗细菌感染，我们现在面临着一个令人担忧的前景：对重要的人类病原体的抗生素耐药性的加速演变和正在开发的新的抗感染药物家族的稀缺。外排是细菌对抗生素产生耐药性的一般机制。这种主动药物转运涉及低内在敏感性、对化学上不相关的分子类别的交叉耐药性以及选择/获得额外的耐药性机制。因此，抑制细菌外排机制似乎是一个有希望的目标，以便（i）增加由外排泵排出的抗生素的细胞内浓度，（ii）恢复耐药临床菌株的药物敏感性，以及（iii）降低获得性额外耐药性的能力。在过去的十年中，已经描述和测试了结构上不相关的外排泵抑制剂（EPI）类别，包括抗生素底物的一些类似物和新的化学分子。在目前收集的EPI中，考虑到抗生素、泵和细菌方面的结构-活性关系和活性谱，仅研究了少数化合物。虽然大量的努力已经表征了越来越多的细菌外排泵并产生了几种潜在的活性EPI，但它们尚未阐明外排转运和抑制的分子基础。最近的研究泵-底物复合物，三维分辨率的外排泵，合成新的化合物和分子动力学研究可能会产生新的线索，破译和选择新的目标内的efflux机制，并最终，可能会导致在临床上有用的分子。
After several decades of continuously successful antibiotic therapy against bacterial infections, we are now facing a worrying prospect: the accelerated evolution of antibiotic resistance to important human pathogens and the scarcity of new anti-infective drug families under development. Efflux is a general mechanism responsible for bacterial resistance to antibiotics. This active drug transport is involved in low intrinsic susceptibility, cross-resistance to chemically unrelated classes of molecules, and selection/acquisition of additional mechanisms of resistance. Thus, inhibition of bacterial efflux mechanisms appears to be a promising target in order to (i) increase the intracellular concentration of antibiotics that are expelled by efflux pumps, (ii) restore the drug susceptibility of resistant clinical strains, and (iii) reduce the capability for acquired additional resistance. Structurally unrelated classes of efflux pump inhibitors (EPIs) have been described and tested in the last decade, including some analogues of antibiotic substrates and new chemical molecules. Among the current collection of EPIs, only a few compounds have been studied taking into account the structure-activity relationships and the spectrum of activity in terms of antibiotics, pumps and bacteria. While large efforts have characterized an increasing number of bacterial eff lux pumps and generated several potentially active EPIs, they have not elucidated the molecular basis of efflux transport and inhibition. Recent studies of pump-substrate complexes, the 3D resolution of the efflux pumps, the synthesis of novel compounds and molecular dynamic studies may generate new clues to decipher and select novel targets inside the eff lux mechanisms and, finally, may result in a clinically useful molecule.