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

Proceedings of the National Academy of Sciences of the United States of America
Jessica M A BlairLaura J V Piddock

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 eff...Continue Reading

References

Jun 16, 1990·Lancet·L J PiddockR Wise
Apr 1, 1988·Antimicrobial Agents and Chemotherapy·J S Chapman, N H Georgopapadakou
Dec 5, 1993·Journal of Molecular Biology·A Sali, T L Blundell
Apr 1, 1993·Antimicrobial Agents and Chemotherapy·L J PiddockY F Jin
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Apr 1, 1996·Antimicrobial Agents and Chemotherapy·D J GriggsL J Piddock
May 13, 1999·Bioinformatics·P GouetF Métoz
Aug 31, 2000·Journal of Molecular Biology·C NotredameJ Heringa
Aug 2, 2001·Journal of Molecular Biology·F SterponeM Marchi
May 25, 2004·Antimicrobial Agents and Chemotherapy·Tahar van der StraatenJaap T van Dissel
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Apr 14, 2006·Cellular Microbiology·Anthony M BuckleyLaura J V Piddock
Jul 15, 2006·The Journal of Antimicrobial Chemotherapy·J M Andrews, UNKNOWN BASC Working Party on Susceptibility Testing
Nov 1, 2006·Protein Science : a Publication of the Protein Society·Min-Yi Shen, Andrej Sali
Dec 30, 2006·PLoS Biology·Gaby SennhauserMarkus G Grütter
Jun 10, 2009·Bioinformatics·Heng LiUNKNOWN 1000 Genome Project Data Processing Subgroup
Jan 30, 2010·Bioinformatics·Aaron R Quinlan, Ira M Hall
Aug 23, 2011·Journal of Bacteriology·Fasahath HusainHiroshi Nikaido
Mar 6, 2012·Nature Methods·Ben Langmead, Steven L Salzberg
Mar 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Thomas EicherKlaas M Pos
Nov 24, 2012·Proceedings of the National Academy of Sciences of the United States of America·Attilio V Vargiu, Hiroshi Nikaido
Jan 10, 2013·PloS One·Francesca ColluPaolo Ruggerone
Mar 16, 2013·The Journal of Antimicrobial Chemotherapy·A J LawlerL J V Piddock
May 23, 2013·Biotechnology for Biofuels·Jee Loon Foo, Susanna Su Jan Leong
Jul 3, 2013·Annual Review of Microbiology·Philip HinchliffeVassilis Koronakis
Jul 3, 2013·Nature·Ryosuke NakashimaAkihito Yamaguchi
Nov 10, 2013·Current Topics in Medicinal Chemistry·Paolo RuggeroneAttilio V Vargiu

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Citations

Sep 16, 2015·International Journal of Molecular Sciences·Gang ZhouXiao-Bao Xie
Jul 21, 2015·Annals of the New York Academy of Sciences·David C Hooper, George A Jacoby
May 18, 2016·FEMS Microbiology Letters·Takashi MatsubaYasuhiko Suzuki
Sep 14, 2016·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Sara Hernando-AmadoJosé L Martínez
Oct 30, 2016·Biochemical and Biophysical Research Communications·Alfred D KinanaHiroshi Nikaido
Nov 29, 2016·Clinical Microbiology and Infection : the Official Publication of the European Society of Clinical Microbiology and Infectious Diseases·M J EllingtonN Woodford
Oct 9, 2015·PLoS Biology·Richard William MeekLaura Jane Violet Piddock
Feb 8, 2018·Experimental Biology and Medicine·Nathan P CoussensDayle A Daines
Apr 12, 2017·Antimicrobial Agents and Chemotherapy·Julia V BugryshevaLinda M Weigel
Feb 10, 2016·Antimicrobial Agents and Chemotherapy·François GuérinJean-Christophe Giard
Aug 8, 2018·Antimicrobial Agents and Chemotherapy·Fernando Sanz-GarcíaJosé Luis Martínez
Jul 7, 2016·MBio·Jessica M A Blair, Laura J V Piddock
Sep 16, 2015·Antimicrobial Agents and Chemotherapy·Matthias WillmannSilke Peter
Oct 17, 2018·Natural Product Reports·Yuan LiuKui Zhu
Oct 26, 2018·The Journal of Antimicrobial Chemotherapy·Boas C L van der PuttenConstance Schultsz
Aug 31, 2016·Nature Microbiology·Laura J V Piddock
Jun 23, 2019·Molecular Biology and Evolution·Sara Hernando-AmadoJosé Luis Martínez
Jun 22, 2018·Journal of the Royal Society, Interface·François BlanquartChristophe Fraser
Mar 8, 2017·Molecular Systems Biology·Mattia ZampieriUwe Sauer
Sep 11, 2019·Molecular Biology and Evolution·Lei SunSebastian Bonhoeffer
Feb 20, 2020·Future Microbiology·Abigail L ColcloughJessica Ma Blair
Feb 14, 2020·Expert Review of Anti-infective Therapy·Teresa Gil-GilPaula Blanco
Feb 6, 2017·Journal of Physics. Condensed Matter : an Institute of Physics Journal·Mariano Andrea ScorciapinoMatteo Ceccarelli
Jul 2, 2020·Transactions of the Royal Society of Tropical Medicine and Hygiene·Robab AzargunShirin Eyvazi
Jul 28, 2016·Cold Spring Harbor Perspectives in Medicine·David C Hooper, George A Jacoby
Jun 19, 2019·Applied Microbiology and Biotechnology·Heba Abdel-HalimSuzanne Abdelmalek
Jul 2, 2020·Infection and Drug Resistance·Ehsaneh KhodadadiHossein Samadi Kafil
Oct 8, 2015·Protein Science : a Publication of the Protein Society·Jared A Delmar, Edward W Yu
Jul 14, 2018·Nature Reviews. Microbiology·Dijun DuBen F Luisi
Jun 19, 2018·Frontiers in Microbiology·Venkata K RamaswamyPaolo Ruggerone

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