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Cryo-EM Structure and Molecular Dynamics Analysis of the Fluoroquinolone Resistant Mutant of the AcrB Transporter from Salmonella

Johnson, Rachel M and Fais, Chiara and Parmar, Mayuriben and Cheruvara, Harish and Marshall, Robert L and Hesketh, Sophie J and Feasey, Matthew C and Ruggerone, Paolo and Vargiu, Attilio V and Postis, Vincent LG and Muench, Stephen P and Bavro, Vassiliy N (2020) 'Cryo-EM Structure and Molecular Dynamics Analysis of the Fluoroquinolone Resistant Mutant of the AcrB Transporter from Salmonella.' Microorganisms, 8 (6). ISSN 2076-2607

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Abstract

Salmonella is an important genus of Gram-negative pathogens, treatment of which has become problematic due to increases in antimicrobial resistance. This is partly attributable to the overexpression of tripartite efflux pumps, particularly the constitutively expressed AcrAB-TolC. Despite its clinical importance, the structure of the Salmonella AcrB transporter remained unknown to-date, with much of our structural understanding coming from the Escherichia coli orthologue. Here, by taking advantage of the styrene maleic acid (SMA) technology to isolate membrane proteins with closely associated lipids, we report the very first experimental structure of Salmonella AcrB transporter. Furthermore, this novel structure provides additional insight into mechanisms of drug efflux as it bears the mutation (G288D), originating from a clinical isolate of Salmonella Typhimurium presenting an increased resistance to fluoroquinolones. Experimental data are complemented by state-of-the-art molecular dynamics (MD) simulations on both the wild type and G288D variant of Salmonella AcrB. Together, these reveal several important differences with respect to the E. coli protein, providing insights into the role of the G288D mutation in increasing drug efflux and extending our understanding of the mechanisms underlying antibiotic resistance.

Item Type: Article
Uncontrolled Keywords: Salmonella; multidrug efflux pump; membrane proteins; multidrug resistance; AcrB; cryo-EM; molecular dynamics
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 23 Jun 2020 20:58
Last Modified: 23 Jun 2020 21:15
URI: http://repository.essex.ac.uk/id/eprint/27952

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