Issue 27, 2022

Recognition of quinolone antibiotics by the multidrug efflux transporter MexB of Pseudomonas aeruginosa

Abstract

The drug/proton antiporter MexB is the engine of the major efflux pump MexAB-OprM in Pseudomonas aeruginosa. This protein is known to transport a large variety of compounds, including antibiotics, thus conferring a multi-drug resistance phenotype. Due to the difficulty of producing co-crystals, only two X-ray structures of MexB in a complex with ligands are available to date, and mechanistic aspects are largely hypothesized based on the body of data collected for the homologous protein AcrB of Escherichia coli. In particular, a recent study (Ornik-Cha, Wilhelm, Kobylka et al., Nat. Commun., 2021, 12, 6919) reported a co-crystal structure of AcrB in a complex with levofloxacin, an antibiotic belonging to the important class of (fluoro)-quinolones. In this work, we performed a systematic ensemble docking campaign coupled to the cluster analysis and molecular-mechanics optimization of docking poses to study the interaction between 36 quinolone antibiotics and MexB. We additionally investigated surface complementarity between each molecule and the transporter and thoroughly assessed the computational protocol adopted against the known experimental data. Our study reveals different binding preferences of the investigated compounds towards the sub-sites of the large deep binding pocket of MexB, supporting the hypothesis that MexB substrates oscillate between different binding modes with similar affinity. Interestingly, small changes in the molecular structure translate into significant differences in MexB–quinolone interactions. All the predicted binding modes are available for download and visualization at the following link: https://www.dsf.unica.it/dock/mexb/quinolones.

Graphical abstract: Recognition of quinolone antibiotics by the multidrug efflux transporter MexB of Pseudomonas aeruginosa

Supplementary files

Article information

Article type
Paper
Submitted
25 2月 2022
Accepted
13 5月 2022
First published
29 6月 2022
This article is Open Access
Creative Commons BY-NC license

Phys. Chem. Chem. Phys., 2022,24, 16566-16575

Recognition of quinolone antibiotics by the multidrug efflux transporter MexB of Pseudomonas aeruginosa

S. Gervasoni, G. Malloci, A. Bosin, A. V. Vargiu, H. I. Zgurskaya and P. Ruggerone, Phys. Chem. Chem. Phys., 2022, 24, 16566 DOI: 10.1039/D2CP00951J

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