Efflux Mediated Co-resistance

  • Amit Gaurav
  • Atin Sharma
  • Ranjana PathaniaEmail author


Antimicrobial resistance is one of the major threats to the global health care facilities. The drug resistant microbes take a heavy toll on the human life resulting in huge losses in terms of economy and human resource. Moreover, with current celerity of mobility, the dissemination of these microbes is relatively easy and swift, making the situation even worse. The rising rate of incidence of ‘superbugs’ that are resistant to all known drugs and dwindling supply of newer antimicrobials, the post-antibiotic era seems an inevitable future. Due to its widespread reach and rapidity, the evolution of antimicrobial resistance (AMR) in bacteria is of particular interest. These microbes resist the action of antimicrobials by various mechanisms, one of which is actively pumping out the antimicrobials from the cellular milieu. This is achieved by specialized proteins, called the efflux pumps, which avoid the effective build-up of antimicrobials and assist survival in otherwise inhibitory concentration of the antimicrobial. These pumps can either be chromosomally encoded or plasmid borne and are generally overexpressed in antimicrobial challenged bacteria. The most striking feature of these efflux pumps is the loss of substrate specificity that enables one pump to efflux out multiple antibiotics. This review focuses on the ability of these pumps to identify multiple substrates and provide selective advantage to the pathogenic bacterial cells.


Antibiotic resistance Efflux pumps Bacteria Heavy metals Metal resistance Biocides Transporters 


  1. Abraham EP, Chain E (1988) An Enzyme from Bacteria Able to Destroy Penicillin. Rev Infect Dis 10:677–678CrossRefGoogle Scholar
  2. Abramson J, Smirnova I, Kasho V, Verner G, Kaback HR, Iwata S (2003) Structure and Mechanism of the Lactose Permease of Escherichia coli. Science 301:610–615. Scholar
  3. Aendekerk S, Ghysels B, Cornelis P, Baysse C (2002) Characterization of a new efflux pump, MexGHI-OpmD, from Pseudomonas aeruginosa that confers resistance to vanadium. Microbiol Read Engl 148:2371–2381. Scholar
  4. Alav I, Sutton JM, Rahman KM (2018) Role of bacterial efflux pumps in biofilm formation. J Antimicrob Chemother 73:2003–2020. Scholar
  5. Allen HK, Donato J, Wang HH, Cloud-Hansen KA, Davies J, Handelsman J (2010) Call of the wild: antibiotic resistance genes in natural environments. Nat Rev Microbiol 8:251–259. Scholar
  6. Baroud M, Dandache I, Araj GF, Wakim R, Kanj S, Kanafani Z, Khairallah M, Sabra A, Shehab M, Dbaibo G, Matar GM (2013) Underlying mechanisms of carbapenem resistance in extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Escherichia coli isolates at a tertiary care centre in Lebanon: role of OXA-48 and NDM-1 carbapenemases. Int J Antimicrob Agents 41:75–79. Scholar
  7. Bay DC, Turner RJ (2012) Small multidrug resistance protein EmrE reduces host pH and osmotic tolerance to metabolic quaternary cation osmoprotectants. J Bacteriol 194:5941–5948. Scholar
  8. Blair JMA, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJV (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13:42–51. Scholar
  9. Buckley AM, Webber MA, Cooles S, Randall LP, La Ragione RM, Woodward MJ, Piddock LJV (2006) The AcrAB-TolC efflux system of Salmonella enterica serovar Typhimurium plays a role in pathogenesis. Cell Microbiol 8:847–856. Scholar
  10. Burse A, Weingart H, Ullrich MS (2004) The phytoalexin-inducible multidrug efflux pump AcrAB contributes to virulence in the fire blight pathogen, Erwinia amylovora. Mol Plant-Microbe Interact MPMI 17:43–54. Scholar
  11. Butaye P, Devriese LA, Haesebrouck F (2003) Antimicrobial growth promoters used in animal feed: effects of less well known antibiotics on gram-positive bacteria. Clin Microbiol Rev 16:175–188. Scholar
  12. Cannon RD, Lamping E, Holmes AR, Niimi K, Baret PV, Keniya MV, Tanabe K, Niimi M, Goffeau A, Monk BC (2009) Efflux-mediated antifungal drug resistance. Clin Microbiol Rev 22:291–321. Scholar
  13. Chan YY, Bian HS, Tan TMC, Mattmann ME, Geske GD, Igarashi J, Hatano T, Suga H, Blackwell HE, Chua KL (2007) Control of quorum sensing by a Burkholderia pseudomallei multidrug efflux pump. J Bacteriol 189:4320–4324. Scholar
  14. Chapman JS (2003) Disinfectant resistance mechanisms, cross-resistance, and co-resistance. Int Biodeterior Biodegrad, Hyg Disinfect 51:271–276. Scholar
  15. D’Costa VM, King CE, Kalan L, Morar M, Sung WWL, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding GB, Poinar HN, Wright GD (2011) Antibiotic resistance is ancient. Nature 477:457–461. Scholar
  16. Davies J, Davies D (2010) Origins and Evolution of Antibiotic Resistance. Microbiol Mol Biol Rev 74:417–433. Scholar
  17. Dolejska M, Villa L, Poirel L, Nordmann P, Carattoli A (2013) Complete sequencing of an IncHI1 plasmid encoding the carbapenemase NDM-1, the ArmA 16S RNA methylase and a resistance–nodulation–cell division/multidrug efflux pump. J Antimicrob Chemother 68:34–39. Scholar
  18. Du D, Wang Z, James NR, Voss JE, Klimont E, Ohene-Agyei T, Venter H, Chiu W, Luisi BF (2014) Structure of the AcrAB–TolC multidrug efflux pump. Nature 509:512–515. Scholar
  19. Fang L, Li X, Li L, Li S, Liao X, Sun J, Liu Y (2016) Co-spread of metal and antibiotic resistance within ST3-IncHI2 plasmids from E. coli isolates of food-producing animals. Sci Rep 6(25312).
  20. Forsberg KJ, Reyes A, Wang B, Selleck EM, Sommer MOA, Dantas G (2012) The shared antibiotic resistome of soil bacteria and human pathogens. Science 337:1107–1111. Scholar
  21. Gandra S, Tseng KK, Arora A, Bhowmik B, Robinson ML, Panigrahi B, Laxminarayan R, Klein EY (2018) The mortality burden of multidrug-resistant pathogens in India: a retrospective observational study. Clin Infect Dis Off Publ Infect Dis Soc Am. Scholar
  22. Gottesman MM, Ling V (2006) The molecular basis of multidrug resistance in cancer: the early years of P-glycoprotein research. FEBS Lett 580:998–1009. Scholar
  23. Hao X, Lüthje F, Rønn R, German NA, Li X, Huang F, Kisaka J, Huffman D, Alwathnani HA, Zhu Y-G, Rensing C (2016) A role for copper in protozoan grazing – two billion years selecting for bacterial copper resistance. Mol Microbiol 102:628–641. Scholar
  24. Higgins CF (2007) Multiple molecular mechanisms for multidrug resistance transporters. Nature 446:749–757. Scholar
  25. Hirakata Y, Srikumar R, Poole K, Gotoh N, Suematsu T, Kohno S, Kamihira S, Hancock REW, Speert DP (2002) Multidrug efflux systems play an important role in the invasiveness of Pseudomonas aeruginosa. J Exp Med 196:109–118CrossRefGoogle Scholar
  26. Jerse AE, Sharma ND, Simms AN, Crow ET, Snyder LA, Shafer WM (2003) A gonococcal efflux pump system enhances bacterial survival in a female mouse model of genital tract infection. Infect Immun 71:5576–5582CrossRefGoogle Scholar
  27. Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162CrossRefGoogle Scholar
  28. Kapur V, Li LL, Iordanescu S, Hamrick MR, Wanger A, Kreiswirth BN, Musser JM (1994) Characterization by automated DNA sequencing of mutations in the gene (rpoB) encoding the RNA polymerase beta subunit in rifampin-resistant Mycobacterium tuberculosis strains from New York City and Texas. J Clin Microbiol 32:1095–1098PubMedPubMedCentralGoogle Scholar
  29. Kobayashi N, Nishino K, Yamaguchi A (2001) Novel macrolide-specific ABC-type efflux transporter inEscherichia coli. J Bacteriol 183:5639–5644. Scholar
  30. Kojima S, Nikaido H (2013) Permeation rates of penicillins indicate that Escherichia coli porins function principally as nonspecific channels. Proc Natl Acad Sci U S A 110:E2629–E2634. Scholar
  31. Kumar N, Radhakrishnan A, Wright CC, Chou T-H, Lei H-T, Bolla JR, Tringides ML, Rajashankar KR, Su C-C, Purdy GE, Yu EW (2014) Crystal structure of the transcriptional regulator Rv1219c of Mycobacterium tuberculosis. Protein Sci Publ Protein Soc 23:423–432. Scholar
  32. Kuroda T, Tsuchiya T (2009) Multidrug efflux transporters in the MATE family. Biochim Biophys Acta BBA Proteins Proteom Mechan Drug Efflux Strateg Combat Them 1794:763–768. Scholar
  33. Lambert PA (2005) Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev 57:1471–1485. Scholar
  34. Lavigne J-P, Sotto A, Nicolas-Chanoine M-H, Bouziges N, Pagès J-M, Davin-Regli A (2013) An adaptive response of Enterobacter aerogenes to imipenem: regulation of porin balance in clinical isolates. Int J Antimicrob Agents 41:130–136. Scholar
  35. Lee LJ, Barrett JA, Poole RK (2005) Genome-wide transcriptional response of chemostat-cultured Escherichia coli to zinc. J Bacteriol 187:1124–1134. Scholar
  36. Lee C-R, Lee JH, Park M, Park KS, Bae IK, Kim YB, Cha C-J, Jeong BC, Lee SH (2017) Biology of Acinetobacter baumannii: pathogenesis, antibiotic resistance mechanisms, and prospective treatment options. Front Cell Infect Microbiol 7.
  37. Levy SB (1992) Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother 36:695–703CrossRefGoogle Scholar
  38. Li X-Z, Nikaido H (2004) Efflux-mediated drug resistance in bacteria. Drugs 64:159–204. Scholar
  39. Li X-Z, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. Scholar
  40. Li XZ, Livermore DM, Nikaido H (1994) Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother 38:1732–1741CrossRefGoogle Scholar
  41. Li X-Z, Plésiat P, Nikaido H (2015) The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 28:337–418. Scholar
  42. Li L-G, Xia Y, Zhang T (2017) Co-occurrence of antibiotic and metal resistance genes revealed in complete genome collection. ISME J 11:651–662. Scholar
  43. Livermore DM (2008) Defining an extended-spectrum beta-lactamase. Clin Microbiol Infect 14(Suppl 1):3–10. Scholar
  44. Long KS, Poehlsgaard J, Kehrenberg C, Schwarz S, Vester B (2006) The Cfr rRNA methyltransferase confers resistance to Phenicols, Lincosamides, Oxazolidinones, Pleuromutilins, and Streptogramin A antibiotics. Antimicrob Agents Chemother 50:2500–2505. Scholar
  45. Ma D, Cook DN, Alberti M, Pon NG, Nikaido H, Hearst JE (1993) Molecular cloning and characterization of acrA and acrE genes of Escherichia coli. J Bacteriol 175:6299–6313CrossRefGoogle Scholar
  46. Mata MT, Baquero F, Pérez-Díaz JC (2000) A multidrug efflux transporter in Listeria monocytogenes. FEMS Microbiol Lett 187:185–188CrossRefGoogle Scholar
  47. McDonnell G, Russell AD (1999) Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev 12:147–179CrossRefGoogle Scholar
  48. Morita Y, Kodama K, Shiota S, Mine T, Kataoka A, Mizushima T, Tsuchiya T (1998) NorM, a putative multidrug efflux protein, of vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob Agents Chemother 42:1778–1782CrossRefGoogle Scholar
  49. Murakami S, Nakashima R, Yamashita E, Yamaguchi A (2002) Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419:587–593. Scholar
  50. Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A (2006) Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443:173–179. Scholar
  51. Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67:593–656. Scholar
  52. Nikaido H, Basina M, Nguyen V, Rosenberg EY (1998) Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those beta-lactam antibiotics containing lipophilic side chains. J Bacteriol 180:4686–4692PubMedPubMedCentralGoogle Scholar
  53. Norris AL, Serpersu EH (2013) Ligand promiscuity through the eyes of the aminoglycoside N3 acetyltransferase IIa. Protein Sci Publ Protein Soc 22:916–928. Scholar
  54. Pal C, Bengtsson-Palme J, Rensing C, Kristiansson E, Larsson DGJ (2014) BacMet: antibacterial biocide and metal resistance genes database. Nucleic Acids Res 42:D737–D743. Scholar
  55. Paterson DL, van Duin D (2017) China’s antibiotic resistance problems. Lancet Infect Dis 17:351–352. Scholar
  56. Perron K, Caille O, Rossier C, Van Delden C, Dumas J-L, Köhler T (2004) CzcR-CzcS, a two-component system involved in heavy metal and carbapenem resistance in Pseudomonas aeruginosa. J Biol Chem 279:8761–8768. Scholar
  57. Perry JA, Wright GD (2013) The antibiotic resistance “mobilome”: searching for the link between environment and clinic. Front Microbiol 4(138).
  58. Piddock LJV (2006a) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19:382–402. Scholar
  59. Piddock LJV (2006b) Multidrug-resistance efflux pumps – not just for resistance. Nat Rev Microbiol 4:629–636. Scholar
  60. Pitout JD, Laupland KB (2008) Extended-spectrum β-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis 8:159–166. Scholar
  61. Poole K (2005) Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56:20–51. Scholar
  62. Reddy VS, Shlykov MA, Castillo R, Sun EI, Saier MH (2012) The major facilitator superfamily (MFS) revisited. FEBS J 279:2022–2035. Scholar
  63. Rice LB (2008) Federal funding for the study of antimicrobial resistance in nosocomial pathogens: No ESKAPE. J Infect Dis 197:1079–1081. Scholar
  64. Romanowska J, Reuter N, Trylska J (2013) Comparing aminoglycoside binding sites in bacterial ribosomal RNA and aminoglycoside modifying enzymes. Proteins 81:63–80. Scholar
  65. Saier MH, Tran CV, Barabote RD (2006) TCDB: the transporter classification database for membrane transport protein analyses and information. Nucleic Acids Res 34:D181–D186. Scholar
  66. Schembri MA, Kjaergaard K, Klemm P (2003) Global gene expression in Escherichia coli biofilms. Mol Microbiol 48:253–267CrossRefGoogle Scholar
  67. Schuldiner S, Lebendiker M, Yerushalmi H (1997) EmrE, the smallest ion-coupled transporter, provides a unique paradigm for structure-function studies. J Exp Biol 200:335–341PubMedGoogle Scholar
  68. Schuster M, Greenberg EP (2006) A network of networks: quorum-sensing gene regulation in Pseudomonas aeruginosa. Int J Med Microbiol IJMM 296:73–81. Scholar
  69. Sennhauser G, Bukowska MA, Briand C, Grütter MG (2009) Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. J Mol Biol 389:134–145. Scholar
  70. Sharma A, Sharma R, Bhattacharyya T, Bhando T, Pathania R (2017) Fosfomycin resistance in Acinetobacter baumannii is mediated by efflux through a major facilitator superfamily (MFS) transporter-AbaF. J Antimicrob Chemother 72:68–74. Scholar
  71. Sobel ML, Neshat S, Poole K (2005) Mutations in PA2491 (mexS) promote MexT-dependent mexEF-oprN expression and multidrug resistance in a clinical strain of Pseudomonas aeruginosa. J Bacteriol 187:1246–1253. Scholar
  72. Srinivasan VB, Rajamohan G, Gebreyes WA (2009) Role of AbeS, a novel efflux pump of the SMR family of transporters, in resistance to antimicrobial agents in Acinetobacter baumannii. Antimicrob Agents Chemother 53:5312–5316. Scholar
  73. Su X-Z, Chen J, Mizushima T, Kuroda T, Tsuchiya T (2005) AbeM, an H+-coupled Acinetobacter baumannii multidrug efflux pump belonging to the MATE family of transporters. Antimicrob Agents Chemother 49:4362–4364. Scholar
  74. Sulavik MC, Houseweart C, Cramer C, Jiwani N, Murgolo N, Greene J, DiDomenico B, Shaw KJ, Miller GH, Hare R, Shimer G (2001) Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob Agents Chemother 45:1126–1136. Scholar
  75. Sun J, Deng Z, Yan A (2014) Bacterial multidrug efflux pumps: Mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun, Integrative Glycobiol Future Perspect 453:254–267. Scholar
  76. Tabak M, Scher K, Hartog E, Romling U, Matthews KR, Chikindas ML, Yaron S (2007) Effect of triclosan on Salmonella typhimurium at different growth stages and in biofilms. FEMS Microbiol Lett 267:200–206. Scholar
  77. Tal N, Schuldiner S (2009) A coordinated network of transporters with overlapping specificities provides a robust survival strategy. Proc Natl Acad Sci 106:9051–9056. Scholar
  78. Tamber S, Hancock REW (2003) On the mechanism of solute uptake in pseudomonas. Front Biosci J Virtual Libr 8:s472–s483CrossRefGoogle Scholar
  79. Telenti A, Imboden P, Marchesi F, Matter L, Schopfer K, Bodmer T, Lowrie D, Colston MJ, Cole S (1993) Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. The Lancet. Originally published as Volume 1, Issue 8846 341: 647–651. Scholar
  80. The world is running out of antibiotics, WHO report confirms [WWW Document] (n.d.) World Health Organ. Accessed 25 Sept 2018
  81. Tsukagoshi N, Aono R (2000) Entry into and release of solvents by Escherichia coli in an organic-aqueous two-liquid-phase system and substrate specificity of the AcrAB-TolC solvent-extruding pump. J Bacteriol 182:4803–4810CrossRefGoogle Scholar
  82. Tuševljak N, Dutil L, Rajić A, Uhland FC, McClure C, St-Hilaire S, Reid-Smith RJ, McEwen SA (2013) Antimicrobial Use and resistance in aquaculture: findings of a globally administered survey of aquaculture-allied professionals. Zoonoses Public Health 60:426–436. Scholar
  83. Ventola CL (2015) The antibiotic resistance crisis. Pharm Ther 40:277–283Google Scholar
  84. Voulgari E, Poulou A, Koumaki V, Tsakris A (2013) Carbapenemase-producing Enterobacteriaceae: now that the storm is finally here, how will timely detection help us fight back? Future Microbiol 8:27–39. Scholar
  85. Walsh C (2000) Molecular mechanisms that confer antibacterial drug resistance. Nature 406:775–781. Scholar
  86. Walsh TR, Wu Y (2016) China bans colistin as a feed additive for animals. Lancet Infect Dis 16:1102–1103. Scholar
  87. Weigel LM, Steward CD, Tenover FC (1998) gyrA mutations associated with fluoroquinolone resistance in eight species of Enterobacteriaceae. Antimicrob Agents Chemother 42:2661–2667CrossRefGoogle Scholar
  88. Wright GD (2005) Bacterial resistance to antibiotics: enzymatic degradation and modification. Adv Drug Deliv Rev 57:1451–1470. Scholar
  89. Wright GD (2011) Molecular mechanisms of antibiotic resistance. Chem Commun Camb Engl 47:4055–4061. Scholar
  90. Yin Y, He X, Szewczyk P, Nguyen T, Chang G (2006) Structure of the multidrug transporter EmrD from Escherichia coli. Science 312:741–744. Scholar
  91. Zgurskaya HI, Nikaido H (1999) Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli. Proc Natl Acad Sci U S A 96:7190–7195CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Molecular Bacteriology and Chemical Genetics Lab, Department of BiotechnologyIndian Institute of Technology RoorkeeRoorkeeIndia

Personalised recommendations