crossmark The Challenge of Efflux-Mediated Antibiotic Resistance in Gram- Negative Bacteria Downloaded from Xian-Zhi Li,a Patrick Plésiat,b Hiroshi Nikaidoc Human Safety Division, Veterinary Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canadaa; Laboratoire de Bactériologie, Faculté de Médecine-Pharmacie, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, Franceb; Department of Molecular and Cell Biology, University of California, Berkeley, California, USAc SUMMARY ..................................................................................................................................................338 http://cmr.asm.org/ INTRODUCTION ............................................................................................................................................339 BIOCHEMISTRY AND GENETICS OF MULTIDRUG EFFLUX PUMPS ........................................................................................339 Classes of Efflux Pumps...................................................................................................................................339 RND Transporters ........................................................................................................................................340 AcrB of Escherichia coli .................................................................................................................................340 Other RND transporters in E. coli .......................................................................................................................347 MFS Transporters .........................................................................................................................................347 ABC Transporters .........................................................................................................................................348 SMR Transporters.........................................................................................................................................348 MATE Transporters .......................................................................................................................................349 on March 24, 2015 by Univ of California-Berkeley Biosci & Natural Res Lib SYNERGY WITH THE OUTER MEMBRANE BARRIER ........................................................................................................349 Pathways of Drug Influx across the OM ..................................................................................................................349 Drugs Traversing the OM Mainly through Porin Channels ...............................................................................................350 Drugs Traversing the OM through the Lipid Bilayer Region ..............................................................................................351 GAMMAPROTEOBACTERIA: ENTEROBACTERIACEAE .......................................................................................................351 E. coli......................................................................................................................................................351 Fluoroquinolones......................................................................................................................................352 ␤-Lactams .............................................................................................................................................352 Other drugs............................................................................................................................................353 Salmonella spp. ..........................................................................................................................................353 Citrobacter spp. ...........................................................................................................................................353 Enterobacter aerogenes and Enterobacter cloacae.........................................................................................................354 Klebsiella pneumoniae ....................................................................................................................................354 Proteus, Providencia, and Morganella spp. ................................................................................................................356 Serratia marcescens .......................................................................................................................................356 Shigella flexneri............................................................................................................................................356 Yersinia enterocolitica and Yersinia pestis..................................................................................................................356 OTHER GAMMAPROTEOBACTERIA: VIBRIO, AEROMONAS, LEGIONELLA, AND PASTEURELLACEAE .......................................................357 Vibrio spp. ................................................................................................................................................357 Aeromonas spp. ..........................................................................................................................................357 Legionella spp. ...........................................................................................................................................357 Pasteurellaceae ...........................................................................................................................................358 Pasteurella multocida...................................................................................................................................358 Haemophilus influenzae ................................................................................................................................358 GAMMAPROTEOBACTERIA: PSEUDOMONAS, ACINETOBACTER, AND STENOTROPHOMONAS............................................................358 Pseudomonas aeruginosa .................................................................................................................................358 OM permeability.......................................................................................................................................358 RND efflux pumps. ....................................................................................................................................358 (continued) Published 18 March 2015 Citation Li X-Z, Plésiat P, Nikaido H. 18 March 2015. The challenge of efflux- mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev doi:10.1128/CMR.00117-14. Address correspondence to Hiroshi Nikaido, [email protected]. Copyright © 2015, American Society for Microbiology. All Rights Reserved. doi:10.1128/CMR.00117-14 April 2015 Volume 28 Number 2 Clinical Microbiology Reviews cmr.asm.org 337 Li et al. (i) MexAB-OprM .....................................................................................................................................358 (ii) MexXY-OprM(OprA)..............................................................................................................................359 (iii) MexCD-OprJ.....................................................................................................................................360 (iv) MexEF-OprN.....................................................................................................................................361 (v) Other RND pumps ...............................................................................................................................361 Downloaded from Acinetobacter spp. ........................................................................................................................................361 OM permeability.......................................................................................................................................361 RND efflux pumps .....................................................................................................................................362 Non-RND efflux pumps ................................................................................................................................362 Stenotrophomonas maltophilia ...........................................................................................................................363 ALPHAPROTEOBACTERIA: BRUCELLA, BARTONELLA, AND RICKETTSIA ....................................................................................363 Brucella spp. ..............................................................................................................................................364 Bartonella spp. ...........................................................................................................................................364 Rickettsia spp. ............................................................................................................................................364 BETAPROTEOBACTERIA: ACHROMOBACTER, BURKHOLDERIA, AND NEISSERIA ...........................................................................364 http://cmr.asm.org/ Achromobacter spp. ......................................................................................................................................364