Department of Physics, University of Cagliari, 09042 Monserrato (CA), Italy.
Int J Mol Sci. 2020 Jan 29;21(3):860. doi: 10.3390/ijms21030860.
The drug/proton antiporter AcrB, engine of the major efflux pump AcrAB(Z)-TolC of and other bacteria, is characterized by its impressive ability to transport chemically diverse compounds, conferring a multi-drug resistance (MDR) phenotype. Although hundreds of small molecules are known to be AcrB substrates, only a few co-crystal structures are available to date. Computational methods have been therefore intensively employed to provide structural and dynamical fingerprints related to transport and inhibition of AcrB. In this work, we performed a systematic computational investigation to study the interaction between representative carbapenem antibiotics and AcrB. We focused on the interaction of carbapenems with the so-called distal pocket, a region known for its importance in binding inhibitors and substrates of AcrB. Our findings reveal how the different physico-chemical nature of these antibiotics is reflected on their binding preference for AcrB. The molecular-level information provided here could help design new antibiotics less susceptible to the efflux mechanism.
药物/质子反向转运蛋白 AcrB 是 和其他细菌主要外排泵 AcrAB(Z)-TolC 的动力，其能够运输化学性质差异极大的化合物的能力令人印象深刻，赋予了多药耐药（MDR）表型。尽管已知有数百种小分子是 AcrB 的底物，但迄今为止只有少数共晶结构可用。因此，计算方法被广泛用于提供与 AcrB 的运输和抑制相关的结构和动力学特征。在这项工作中，我们进行了系统的计算研究，以研究代表性碳青霉烯类抗生素与 AcrB 之间的相互作用。我们专注于碳青霉烯类抗生素与所谓的远端口袋的相互作用，该区域已知对结合 AcrB 的抑制剂和底物很重要。我们的发现揭示了这些抗生素的不同物理化学性质如何反映在它们对 AcrB 的结合偏好上。这里提供的分子水平信息有助于设计不易受外排机制影响的新抗生素。
