Analysis of AcrB in Klebsiella pneumoniae reveals natural variants promoting enhanced multidrug resistance.
Analysis of AcrB in Klebsiella pneumoniae reveals natural variants promoting enhanced multidrug resistance.
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DOI：
10.1016/j.resmic.2021.103901
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发表时间：
2022-03
影响因子：
2.6
通讯作者：
Dorr, Tobias
中科院分区：
文献类型：
--
作者：
Li, Ying;Cross, Trevor S.;Dorr, Tobias
由肺炎克雷伯菌引起的感染通常难以管理，这是由于经常由外排泵引起的高频率的多药耐药性。在这项研究中，我们分析了主要的RND家族多药外排泵AcrB的387组装K。pneumoniae基因组。我们证实AcrB是K. pneumoniae，并鉴定了在临床分离株中流行的几种变体。对其中两种变体（L118M和S966A）的分子动力学分析表明，构象变化可能与药物外排能力增加相关。L118M的改变导致蛋白质刚性增强，而药物结合口袋的柔性稳定或增加，并且近端口袋与水分子之间的相互作用更强。对于S966A，显著增大的近端囊袋表明更高的药物容纳能力。与这些预测一致，L118M和S966A变体赋予在四环素存在下生长的略微增加的能力，并且当过表达时在头孢西丁暴露下存活。总之，我们的研究结果表明，功能增强型AcrB变异体的出现可能是临床克雷伯菌抗生素耐药性增加的潜在风险。肺炎分离株。
Infections caused by Klebsiella pneumoniae are often difficult to manage due to the high frequency of multidrug resistance, often conferred by efflux pumps. In this study, we analyzed sequence variations of the major RND family multidrug efflux pump AcrB from 387 assembled K. pneumoniae genomes. We confirm that AcrB is a highly-conserved efflux pump in K. pneumoniae, and identified several variants that were prevalent in clinical isolates. Molecular dynamics analyses on two of these variants (L118M and S966A) suggested conformational changes that may correlate with increased drug efflux capabilities. The L118M change resulted in enhanced protein rigidity while the flexibility of drug binding pockets was stable or increased, and the interactions between the proximal pockets and water molecules were stronger. For S966A, the significantly enlarged proximal pocket suggested higher drug accommodation ability. Consistent with these predictions, the L118M and S966A variants conferred a slightly increased ability to grow in the presence of tetracycline and to survive cefoxitin exposure when overexpressed. In summary, our results suggest that the emergence of enhanced-function AcrB variants may be a potential risk for increased antibiotic resistance in clinical K. pneumoniae isolates.
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影响因子：
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作者：
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