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AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity.

Blair, Jessica MA and Bavro, Vassiliy N and Ricci, Vito and Modi, Niraj and Cacciotto, Pierpaolo and Kleinekathӧfer, Ulrich and Ruggerone, Paolo and Vargiu, Attilio V and Baylay, Alison J and Smith, Helen E and Brandon, Yvonne and Galloway, David and Piddock, Laura JV (2015) 'AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity.' Proceedings of the National Academy of Sciences, 112 (11). 3511 - 3516. ISSN 0027-8424

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Abstract

The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-TolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.

Item Type: Article
Uncontrolled Keywords: Humans, Escherichia coli, Salmonella enterica, Water, Ciprofloxacin, Doxorubicin, Minocycline, Bacterial Proteins, Escherichia coli Proteins, Membrane Transport Proteins, Multidrug Resistance-Associated Proteins, Anti-Bacterial Agents, Microbial Sensitivity Tests, Amino Acid Substitution, Drug Resistance, Multiple, Bacterial, Binding Sites, Substrate Specificity, Mutation, Polymorphism, Single Nucleotide, Genome, Bacterial, Models, Molecular, Genetic Fitness
Subjects: Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 06 Oct 2016 16:05
Last Modified: 28 Jun 2021 13:15
URI: http://repository.essex.ac.uk/id/eprint/17728

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