Molecular Mechanism of MBX2319 Inhibition of Escherichia coli AcrB Multidrug Efflux Pump and Comparison with Other Inhibitors
Molecular Mechanism of MBX2319 Inhibition of Escherichia coli AcrB Multidrug Efflux Pump and Comparison with Other Inhibitors
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DOI：
10.1128/aac.03283-14
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发表时间：
2014-10-01
影响因子：
4.9
通讯作者：
Nikaido, Hiroshi
中科院分区：
文献类型：
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作者：
Vargiu, Attilio V.;Ruggerone, Paolo;Nikaido, Hiroshi
耐药结瘤分裂（RND）超家族的外排泵，如AcrB，在革兰氏阴性菌的多药耐药中起重要作用。RND泵抑制剂的开发将提高当前和下一代抗生素的疗效。然而，迄今为止，只有一种抑制剂与AcrB共结晶。因此，基于硅结构的分析对于阐明其他抑制剂与外排泵之间的相互作用是必不可少的。在这项工作中，我们使用计算机对接和分子动力学模拟来研究AcrB与化合物MBX2319之间的相互作用，MBX2319是一种新型pyranopyridine外排泵抑制剂，对肠杆菌科物种的RND外排泵具有有效活性，以及其他已知抑制剂（D13-9001, 1-[1-萘甲基]-哌嗪和苯丙酰精氨酸- β -萘酰胺）以及阿霉素与AcrB外排缺陷F610A变体的结合。我们还分析了底物米诺环素的结合情况，以进行比较。我们的研究结果表明，MBX2319与AcrB的B原聚物远端袋的下部结合非常紧密，与疏水陷阱衬里的苯丙氨酸有强烈的相互作用，其中D13-9001的疏水部分通过x射线晶体学发现结合。此外，MBX2319结合AcrB的方式与阿霉素结合AcrB的F610A变体的方式相似。相比之下，与MBX2319相比，1-（1-萘甲基）-哌嗪和苯丙酰精氨酸- β -萘酰胺似乎与AcrB B原聚体远端口袋的结合区域有所不同。然而，所有抑制剂（D13-9001除外）似乎都扭曲了远端囊的结构，损害了底物的正常结合。
Efflux pumps of the resistance nodulation division (RND) superfamily, such as AcrB, make a major contribution to multidrug resistance in Gram-negative bacteria. The development of inhibitors of the RND pumps would improve the efficacy of current and next-generation antibiotics. To date, however, only one inhibitor has been cocrystallized with AcrB. Thus, in silico structure-based analysis is essential for elucidating the interaction between other inhibitors and the efflux pumps. In this work, we used computer docking and molecular dynamics simulations to study the interaction between AcrB and the compound MBX2319, a novel pyranopyridine efflux pump inhibitor with potent activity against RND efflux pumps of Enterobacteriaceae species, as well as other known inhibitors (D13-9001, 1-[1-naphthylmethyl]-piperazine, and phenylalanylarginine-beta-naphthylamide) and the binding of doxorubicin to the efflux-defective F610A variant of AcrB. We also analyzed the binding of a substrate, minocycline, for comparison. Our results show that MBX2319 binds very tightly to the lower part of the distal pocket in the B protomer of AcrB, strongly interacting with the phenylalanines lining the hydrophobic trap, where the hydrophobic portion of D13-9001 was found to bind by X-ray crystallography. Additionally, MBX2319 binds to AcrB in a manner that is similar to the way in which doxorubicin binds to the F610A variant of AcrB. In contrast, 1-(1-naphthylmethyl)-piperazine and phenylalanylarginine-beta-naphthylamide appear to bind to somewhat different areas of the distal pocket in the B protomer of AcrB than does MBX2319. However, all inhibitors (except D13-9001) appear to distort the structure of the distal pocket, impairing the proper binding of substrates.