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

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AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. / Blair, Jessica M. A.; Bavro, Vassiliy N.; Ricci, Vito; Modi, Niraj; Cacciotto, Pierpaolo; Kleinekathӧfer, Ulrich; Ruggerone, Paolo; Vargiu, Attilio V.; Baylay, Alison J.; Smith, Helen E.; Brandon, Yvonne; Galloway, David; Piddock, Laura J. V.

In: National Academy of Sciences. Proceedings, Vol. 112, No. 11, 17.03.2015, p. 3511-3516.

Research output: Contribution to journalArticlepeer-review

Harvard

Blair, JMA, Bavro, VN, Ricci, V, Modi, N, Cacciotto, P, Kleinekathӧfer, U, Ruggerone, P, Vargiu, AV, Baylay, AJ, Smith, HE, Brandon, Y, Galloway, D & Piddock, LJV 2015, 'AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity', National Academy of Sciences. Proceedings, vol. 112, no. 11, pp. 3511-3516. https://doi.org/10.1073/pnas.1419939112

APA

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Author

Blair, Jessica M. A. ; Bavro, Vassiliy N. ; Ricci, Vito ; Modi, Niraj ; Cacciotto, Pierpaolo ; Kleinekathӧfer, Ulrich ; Ruggerone, Paolo ; Vargiu, Attilio V. ; Baylay, Alison J. ; Smith, Helen E. ; Brandon, Yvonne ; Galloway, David ; Piddock, Laura J. V. / AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. In: National Academy of Sciences. Proceedings. 2015 ; Vol. 112, No. 11. pp. 3511-3516.

Bibtex

@article{2824356a7bf24ee9b37495a239c075a7,
title = "AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity",
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.",
keywords = "AcrB, antimicrobial resistance, efflux, whole genome sequencing",
author = "Blair, {Jessica M. A.} and Bavro, {Vassiliy N.} and Vito Ricci and Niraj Modi and Pierpaolo Cacciotto and Ulrich Kleinekathӧfer and Paolo Ruggerone and Vargiu, {Attilio V.} and Baylay, {Alison J.} and Smith, {Helen E.} and Yvonne Brandon and David Galloway and Piddock, {Laura J. V.}",
year = "2015",
month = mar,
day = "17",
doi = "10.1073/pnas.1419939112",
language = "English",
volume = "112",
pages = "3511--3516",
journal = "Proceedings of the National Academy of Sciences",
issn = "1091-6490",
publisher = "National Academy of Sciences",
number = "11",

}

RIS

TY - JOUR

T1 - AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

AU - Blair, Jessica M. A.

AU - Bavro, Vassiliy N.

AU - Ricci, Vito

AU - Modi, Niraj

AU - Cacciotto, Pierpaolo

AU - Kleinekathӧfer, Ulrich

AU - Ruggerone, Paolo

AU - Vargiu, Attilio V.

AU - Baylay, Alison J.

AU - Smith, Helen E.

AU - Brandon, Yvonne

AU - Galloway, David

AU - Piddock, Laura J. V.

PY - 2015/3/17

Y1 - 2015/3/17

N2 - 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.

AB - 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.

KW - AcrB

KW - antimicrobial resistance

KW - efflux

KW - whole genome sequencing

U2 - 10.1073/pnas.1419939112

DO - 10.1073/pnas.1419939112

M3 - Article

C2 - 25737552

VL - 112

SP - 3511

EP - 3516

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 11

ER -