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Antimicrobial Drug Efflux Pumps in Escherichia coli

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Efflux-Mediated Antimicrobial Resistance in Bacteria

Abstract

Bacterial active efflux of drugs (encoded by plasmids) was first discovered in Escherichia coli. Subsequently, a large number of chromosomally encoded multidrug efflux pumps (represented by AcrAB-TolC system) were identified in this species. Several of these efflux systems have served as prototypical pumps for characterizing substrate specificity, transport mechanisms, regulation, and inhibition of bacterial drug transporters. Efflux pumps are encoded by chromosomes or plasmids and exhibit a variable (broad or narrow) drug substrate profile that can be clinically relevant. Physiological roles of certain pumps have been demonstrated. This chapter provides an updated overview of more than 20 individual efflux systems/pumps of various families in E. coli with a focus on their substrate profiles, clinical relevance, and expression-based regulation. A discussion is also made on the interplay between the AcrAB pump and outer membrane permeability barrier on drug susceptibility as well as the AcrB-catalyzed efflux kinetics for β-lactams in intact cells.

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References

  1. Croxen MA, Law RJ, Scholz R, Keeney KM, Wlodarska M, Finlay BB (2013) Recent advances in understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev 26:822–880. doi:10.1128/CMR.00022-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Levy SB, McMurry L (1978) Plasmid-determined tetracycline resistance involves new transport systems for tetracycline. Nature 276:90–92. doi:10.1038/276090a0

    Article  CAS  PubMed  Google Scholar 

  3. McMurry L, Petrucci RE Jr, Levy SB (1980) Active efflux of tetracycline encoded by four genetically different tetracycline resistance determinants in Escherichia coli. Proc Natl Acad Sci U S A 77:3974–3977. doi:10.1073/pnas.77.7.3974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ball PR, Shales SW, Chopra I (1980) Plasmid-mediated tetracycline resistance in Escherichia coli involves increased efflux of the antibiotic. Biochem Biophys Res Commun 93:74–81. doi:10.1016/S0006-291X(80)80247-6

    Article  CAS  PubMed  Google Scholar 

  5. 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 175:6299–6313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nakamura H (1966) Acriflavine-binding capacity of Escherichia coli in relation to acriflavine sensitivity and metabolic activity. J Bacteriol 92:1447–1452

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Watanabe T (1963) Infective heredity of multiple drug resistance in bacteria. Bacteriol Rev 27:87–115

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Levy SB, McMurry L (1974) Detection of an inducible membrane protein associated with R-factor-mediated tetracycline resistance. Biochem Biophys Res Commun 56:1060–1068. doi:10.1016/S0006-291X(74)80296-2

    Article  CAS  PubMed  Google Scholar 

  9. Nakamura H (1965) Gene-controlled resistance to acriflavine and other basic dyes in Escherichia coli. J Bacteriol 90:8–14

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Nakamura H (1968) Genetic determination of resistance to acriflavine, phenethyl alcohol, and sodium dodecyl sulfate in Escherichia coli. J Bacteriol 96:987–996

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Nakamura H (1967) Changes in sensitivity to acriflavine of Escherichia coli grown in media of different glucose contents. J Gen Microbiol 49:443–449. doi:10.1099/00221287-49-3-443

    Article  CAS  Google Scholar 

  12. Nakamura H, Suganuma A (1972) Membrane mutation associated with sensitivity to acriflavine in Escherichia coli. J Bacteriol 110:329–335

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Nakamura H, Hachiya N, Tojo T (1978) Second acriflavine sensitivity mutation, acrB, in Escherichia coli K-12. J Bacteriol 134:1184–1187

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nakamura H (1979) Novel acriflavin resistance genes, acrC and acrD, in Escherichia coli K-12. J Bacteriol 139:8–12

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Sukupolvi S, Vaara M (1989) Salmonella typhimurium and Escherichia coli mutants with increased outer membrane permeability to hydrophobic compounds. Biochim Biophys Acta 988:377–387. doi:10.1016/0304-4157(89)90011-7

    Article  CAS  PubMed  Google Scholar 

  16. Nikaido H (1989) Outer membrane barrier as a mechanism of antimicrobial resistance. Antimicrob Agents Chemother 33:1831–1836. doi:10.1128/AAC.33.11.1831

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Okusu H, Ma D, Nikaido H (1996) AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants. J Bacteriol 178:306–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. George AM, Levy SB (1983) Gene in the major cotransduction gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics. J Bacteriol 155:541–548

    CAS  PubMed  PubMed Central  Google Scholar 

  19. George AM, Levy SB (1983) Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics in Escherichia coli: involvement of a non-plasmid-determined efflux of tetracycline. J Bacteriol 155:531–540

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rosner JL (1985) Nonheritable resistance to chloramphenicol and other antibiotics induced by salicylates and other chemotactic repellents in Escherichia coli K-12. Proc Natl Acad Sci U S A 82:8771–8774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Fralick JA (1996) Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli. J Bacteriol 178:5803–5805

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Koronakis V, Eswaran J, Hughes C (2004) Structure and function of TolC: the bacterial exit duct for proteins and drugs. Annu Rev Biochem 73:467–489. doi:10.1146/annurev.biochem.73.011303.074104

    Article  CAS  PubMed  Google Scholar 

  23. Poole K, Krebes K, McNally C, Neshat S (1993) Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon. J Bacteriol 175:7363–7372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li X-Z, 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 38:1732–1741. doi:10.1128/AAC.38.8.1732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li X-Z, Ma D, Livermore DM, Nikaido H (1994) Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to β-lactam resistance. Antimicrob Agents Chemother 38:1742–1752. doi:10.1128/AAC.38.8.1742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pan W, Spratt BG (1994) Regulation of the permeability of the gonococcal cell envelope by the mtr system. Mol Microbiol 11:769–775. doi:10.1111/j.1365-2958.1994.tb00354.x

    Article  CAS  PubMed  Google Scholar 

  27. Nikaido H (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264:382–388. doi:10.1126/science.8153625

    Article  CAS  PubMed  Google Scholar 

  28. Nikaido H (2011) To the happy few. Ann Rev Microbiol 65:1–18. doi:10.1146/annurev-micro-090110-102920

    Article  CAS  Google Scholar 

  29. Ma D, Cook DN, Hearst JE, Nikaido H (1994) Efflux pumps and drug resistance in Gram-negative bacteria. Trends Microbiol 2:489–493. doi:10.1016/0966-842X(94)90654-8

    Google Scholar 

  30. Bentley J, Hyatt LS, Ainley K, Parish JH, Herbert RB, White GR (1993) Cloning and sequence analysis of an Escherichia coli gene conferring bicyclomycin resistance. Gene 127:117–120. doi:10.1016/0378-1119(93)90625-D

    Article  CAS  PubMed  Google Scholar 

  31. Nilsen IW, Bakke I, Vader A, Olsvik O, El-Gewely MR (1996) Isolation of cmr, a novel Escherichia coli chloramphenicol resistance gene encoding a putative efflux pump. J Bacteriol 178:3188–3193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Edgar R, Bibi E (1997) MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition. J Bacteriol 179:2274–2280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lomovskaya O, Lewis K (1992) Emr, an Escherichia coli locus for multidrug resistance. Proc Natl Acad Sci U S A 89:8938–8942. doi:10.1073/pnas.89.19.8938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Naroditskaya V, Schlosser MJ, Fang NY, Lewis K (1993) An E. coli gene emrD is involved in adaptation to low energy shock. Biochem Biophys Res Commun 196:803–809. doi:10.1006/bbrc.1993.2320

    Article  CAS  PubMed  Google Scholar 

  35. Yerushalmi H, Lebendiker M, Schuldiner S (1995) EmrE, an Escherichia coli 12-kDa multidrug transporter, exchanges toxic cations and H+ and is soluble in organic solvents. J Biol Chem 270:6856–6863

    Article  CAS  PubMed  Google Scholar 

  36. Nishino K, Yamaguchi A (2001) Analysis of a complete library of putative drug transporter genes in Escherichia coli. J Bacteriol 183:5803–5812. doi:10.1128/JB.183.20.5803-5812.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sulavik MC, Houseweart C, Cramer C, Jiwani N, Murgolo N, Greene J, DiDomenico B, Shaw KJ et al (2001) Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob Agents Chemother 45:1126–1136. doi:10.1128/AAC.45.4.1126-1136.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Swick MC, Morgan-Linnell SK, Carlson KM, Zechiedrich L (2011) Expression of multidrug efflux pump genes acrAB-tolC, mdfA, and norE in Escherichia coli clinical isolates as a function of fluoroquinolone and multidrug resistance. Antimicrob Agents Chemother 55:921–924. doi:10.1128/AAC.00996-10

    Article  CAS  PubMed  Google Scholar 

  39. Elkins CA, Mullis LB (2006) Mammalian steroid hormones are substrates for the major RND- and MFS-type tripartite multidrug efflux pumps of Escherichia coli. J Bacteriol 188:1191–1195. doi:10.1128/JB.188.3.1191-1195.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Horiyama T, Nishino K (2014) AcrB, AcrD, and MdtABC multidrug efflux systems are involved in enterobactin export in Escherichia coli. PLoS One 9:e108642. doi:10.1371/journal.pone.0108642

    Google Scholar 

  41. Rosenberg EY, Ma D, Nikaido H (2000) AcrD of Escherichia coli is an aminoglycoside efflux pump. J Bacteriol 182:1754–1756. doi:10.1128/JB.182.6.1754-1756.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yamasaki S, Nagasawa S, Hayashi-Nishino M, Yamaguchi A, Nishino K (2011) AcrA dependency of the AcrD efflux pump in Salmonella enterica serovar Typhimurium. J Antibiot (Tokyo) 64:433–437. doi:10.1038/ja.2011.28

    Article  CAS  Google Scholar 

  43. Aires JR, Nikaido H (2005) Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli. J Bacteriol 187:1923–1929. doi:10.1128/JB.187.6.1923-1929.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Matsumura K, Furukawa S, Ogihara H, Morinaga Y (2011) Roles of multidrug efflux pumps on the biofilm formation of Escherichia coli K-12. Biocontrol Sci 16:69–72. doi:10.4265/bio.16.69

    Article  CAS  PubMed  Google Scholar 

  45. Hirata T, Saito A, Nishino K, Tamura N, Yamaguchi A (2004) Effects of efflux transporter genes on susceptibility of Escherichia coli to tigecycline (GAR-936). Antimicrob Agents Chemother 48:2179–2184. doi:10.1128/AAC.48.6.2179-2184.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jellen-Ritter AS, Kern WV (2001) Enhanced expression of the multidrug efflux pumps AcrAB and AcrEF associated with insertion element transposition in Escherichia coli mutants selected with a fluoroquinolone. Antimicrob Agents Chemother 45:1467–1472. doi:10.1128/AAC.45.5.1467-1472.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kobayashi K, Tsukagoshi N, Aono R (2001) Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element. J Bacteriol 183:2646–2653. doi:10.1128/JB.183.8.2646-2653.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lau SY, Zgurskaya HI (2005) Cell division defects in Escherichia coli deficient in the multidrug efflux transporter AcrEF-TolC. J Bacteriol 187:7815–7825. doi:10.1128/JB.187.22.7815-7825.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Viveiros M, Jesus A, Brito M, Leandro C, Martins M, Ordway D, Molnar AM, Molnar J et al (2005) Inducement and reversal of tetracycline resistance in Escherichia coli K-12 and expression of proton gradient-dependent multidrug efflux pump genes. Antimicrob Agents Chemother 49:3578–3582. doi:10.1128/AAC.49.8.3578-3582.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Munson GP, Lam DL, Outten FW, O’Halloran TV (2000) Identification of a copper-responsive two-component system on the chromosome of Escherichia coli K-12. J Bacteriol 182:5864–5871. doi:10.1128/JB.182.20.5864-5871.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Franke S, Grass G, Rensing C, Nies DH (2003) Molecular analysis of the copper-transporting efflux system CusCFBA of Escherichia coli. J Bacteriol 185:3804–3812. doi:10.1128/JB.185.13.3804-3812.2003

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Franke S, Grass G, Nies DH (2001) The product of the ybdE gene of the Escherichia coli chromosome is involved in detoxification of silver ions. Microbiology 147:965–972. doi:10.1099/00221287-147-4-965

    Article  CAS  PubMed  Google Scholar 

  53. Gupta A, Phung LT, Taylor DE, Silver S (2001) Diversity of silver resistance genes in IncH incompatibility group plasmids. Microbiology 147:3393–3402. doi:10.1099/00221287-147-12-3393

    Article  CAS  PubMed  Google Scholar 

  54. Baranova N, Nikaido H (2002) The baeSR two-component regulatory system activates transcription of the yegMNOB (mdtABCD) transporter gene cluster in Escherichia coli and increases its resistance to novobiocin and deoxycholate. J Bacteriol 184:4168–4176. doi:10.1128/JB.184.15.4168-4176.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nagakubo S, Nishino K, Hirata T, Yamaguchi A (2002) The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC. J Bacteriol 184:4161–4167. doi:10.1128/JB.184.15.4161-4167.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Deininger KN, Horikawa A, Kitko RD, Tatsumi R, Rosner JL, Wachi M, Slonczewski JL (2011) A requirement of TolC and MDR efflux pumps for acid adaptation and GadAB induction in Escherichia coli. PLoS One 6:e18960. doi:10.1371/journal.pone.0018960

    Google Scholar 

  57. Lennen RM, Politz MG, Kruziki MA, Pfleger BF (2013) Identification of transport proteins involved in free fatty acid efflux in Escherichia coli. J Bacteriol 195:135–144. doi:10.1128/JB.01477-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhang Y, Xiao M, Horiyama T, Zhang Y, Li X, Nishino K, Yan A (2011) The multidrug efflux pump MdtEF protects against nitrosative damage during the anaerobic respiration in Escherichia coli. J Biol Chem 286:26576–26584. doi:10.1074/jbc.M111.243261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Deng Z, Shan Y, Pan Q, Gao X, Yan A (2013) Anaerobic expression of the gadE-mdtEF multidrug efflux operon is primarily regulated by the two-component system ArcBA through antagonizing the H-NS mediated repression. Front Microbiol 4:194. doi:10.3389/fmicb.2013.00194

    PubMed  PubMed Central  Google Scholar 

  60. Nishino K, Yamasaki S, Hayashi-Nishino M, Yamaguchi A (2011) Effect of overexpression of small non-coding DsrA RNA on multidrug efflux in Escherichia coli. J Antimicrob Chemother 66:291–296. doi:10.1093/jac/dkq420

    Article  CAS  PubMed  Google Scholar 

  61. Bohnert JA, Schuster S, Fahnrich E, Trittler R, Kern WV (2007) Altered spectrum of multidrug resistance associated with a single point mutation in the Escherichia coli RND-type MDR efflux pump YhiV (MdtF). J Antimicrob Chemother 59:1216–1222. doi:10.1093/jac/dkl426

    Article  CAS  PubMed  Google Scholar 

  62. Hansen LH, Johannesen E, Burmolle M, Sørensen AH, Sørensen SJ (2004) Plasmid-encoded multidrug efflux pump conferring resistance to olaquindox in Escherichia coli. Antimicrob Agents Chemother 48:3332–3337. doi:10.1128/AAC.48.9.3332-3337.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sorensen AH, Hansen LH, Johannesen E, Sorensen SJ (2003) Conjugative plasmid conferring resistance to olaquindox. Antimicrob Agents Chemother 47:798–799. doi:10.1128/AAC.47.2.798-799.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hansen LH, Jensen LB, Sørensen HI, Sørensen SJ (2007) Substrate specificity of the OqxAB multidrug resistance pump in Escherichia coli and selected enteric bacteria. J Antimicrob Chemother 60:145–147. doi:10.1093/jac/dkm167

    Article  CAS  PubMed  Google Scholar 

  65. Ho PL, Ng KY, Lo WU, Law PY, Lai EL, Wang Y, Chow KH (2016) Plasmid-mediated OqxAB is an important mechanism for nitrofurantoin resistance in Escherichia coli. Antimicrob Agents Chemother 60:537–543. doi:10.1128/AAC.02156-15

    Article  CAS  Google Scholar 

  66. Hansen LH, Sørensen SJ, Jorgensen HS, Jensen LB (2005) The prevalence of the OqxAB multidrug efflux pump amongst olaquindox-resistant Escherichia coli in pigs. Microb Drug Resist 11:378–382. doi:10.1089/mdr.2005.11.378

    Article  CAS  PubMed  Google Scholar 

  67. Hayashi M, Tabata K, Yagasaki M, Yonetani Y (2010) Effect of multidrug-efflux transporter genes on dipeptide resistance and overproduction in Escherichia coli. FEMS Microbiol Lett 304:12–19. doi:10.1111/j.1574-6968.2009.01879.x

    Article  CAS  PubMed  Google Scholar 

  68. Yamada S, Awano N, Inubushi K, Maeda E, Nakamori S, Nishino K, Yamaguchi A, Takagi H (2006) Effect of drug transporter genes on cysteine export and overproduction in Escherichia coli. Appl Environ Microbiol 72:4735–4742. doi:10.1128/AEM.02507-05

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Phadtare S, Yamanaka K, Kato I, Inouye M (2001) Antibacterial activity of 4,5-dihydroxy-2-cyclopentan-1-one (DHCP) and cloning of a gene conferring DHCP resistance in Escherichia coli. J Mol Microbiol Biotechnol 3:461–465

    CAS  PubMed  Google Scholar 

  70. Horiyama T, Yamaguchi A, Nishino K (2010) TolC dependency of multidrug efflux systems in Salmonella enterica serovar Typhimurium. J Antimicrob Chemother 65:1372–1376. doi:10.1093/jac/dkq160

    Article  CAS  PubMed  Google Scholar 

  71. Furukawa H, Tsay JT, Jackowski S, Takamura Y, Rock CO (1993) Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J Bacteriol 175:3723–3729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Nishino K, Latifi T, Groisman EA (2006) Virulence and drug resistance roles of multidrug efflux systems of Salmonella enterica serovar Typhimurium. Mol Microbiol 59:126–141. doi:10.1111/j.1365-2958.2005.04940.x

    Article  CAS  PubMed  Google Scholar 

  73. Koita K, Rao CV (2012) Identification and analysis of the putative pentose sugar efflux transporters in Escherichia coli. PLoS One 7:e43700. doi:10.1371/journal.pone.0043700

    Google Scholar 

  74. Nishino K, Yamaguchi A (2001) Overexpression of the response regulator evgA of the two-component signal transduction system modulates multidrug resistance conferred by multidrug resistance transporters. J Bacteriol 183:1455–1458. doi:10.1128/JB.183.4.1455-1458.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Han X, Dorsey-Oresto A, Malik M, Wang JY, Drlica K, Zhao X, Lu T (2010) Escherichia coli genes that reduce the lethal effects of stress. BMC Microbiol 10:35. doi:10.1186/1471-2180-10-35

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Nishino K, Yamaguchi A (2004) Role of histone-like protein H-NS in multidrug resistance of Escherichia coli. J Bacteriol 186:1423–1429. doi:10.1128/JB.186.5.1423-1429.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Eguchi Y, Oshima T, Mori H, Aono R, Yamamoto K, Ishihama A, Utsumi R (2003) Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli. Microbiology 149:2819–2828. doi:10.1099/mic.0.26460-0

    Article  CAS  PubMed  Google Scholar 

  78. Blickwede M, Schwarz S (2004) Molecular analysis of florfenicol-resistant Escherichia coli isolates from pigs. J Antimicrob Chemother 53:58–64. doi:10.1093/jac/dkh007

    Article  CAS  PubMed  Google Scholar 

  79. Cloeckaert A, Baucheron S, Flaujac G, Schwarz S, Kehrenberg C, Martel JL, Chaslus-Dancla E (2000) Plasmid-mediated florfenicol resistance encoded by the floR gene in Escherichia coli isolated from cattle. Antimicrob Agents Chemother 44:2858–2860. doi:10.1128/AAC.44.10.2858-2860.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Braibant M, Chevalier J, Chaslus-Dancla E, Pagès JM, Cloeckaert A (2005) Structural and functional study of the phenicol-specific efflux pump FloR belonging to the major facilitator superfamily. Antimicrob Agents Chemother 49:2965–2971. doi:10.1128/AAC.49.7.2965-2971.2005

    Google Scholar 

  81. Bohn C, Bouloc P (1998) The Escherichia coli cmlA gene encodes the multidrug efflux pump Cmr/MdfA and is responsible for isopropyl-β-D-thiogalactopyranoside exclusion and spectinomycin sensitivity. J Bacteriol 180:6072–6075

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Mine T, Morita Y, Kataoka A, Mizushima T, Tsuchiya T (1998) Evidence for chloramphenicol/H+ antiport in Cmr (MdfA) system of Escherichia coli and properties of the antiporter. J Biochem (Tokyo) 124:187–193

    Article  CAS  Google Scholar 

  83. Krulwich TA, Lewinson O, Padan E, Bibi E (2005) Do physiological roles foster persistence of drug/multidrug-efflux transporters? a case study. Nat Rev Microbiol 3:566–572. doi:10.1038/nrmicro1181

    Article  CAS  PubMed  Google Scholar 

  84. Fabrega A, Martin RG, Rosner JL, Tavio MM, Vila J (2010) Constitutive SoxS expression in a fluoroquinolone-resistant strain with a truncated SoxR protein and identification of a new member of the marA-soxS-rob regulon, mdtG. Antimicrob Agents Chemother 54:1218–1225. doi:10.1128/AAC.00944-09

    Article  CAS  PubMed  Google Scholar 

  85. Holdsworth SR, Law CJ (2013) The major facilitator superfamily transporter MdtM contributes to the intrinsic resistance of Escherichia coli to quaternary ammonium compounds. J Antimicrob Chemother 68:831–839. doi:10.1093/jac/dks491

    Article  CAS  PubMed  Google Scholar 

  86. Holdsworth SR, Law CJ (2012) Functional and biochemical characterisation of the Escherichia coli major facilitator superfamily multidrug transporter MdtM. Biochimie 94:1334–1346. doi:10.1016/j.biochi.2012.03.001

    Article  CAS  PubMed  Google Scholar 

  87. Holdsworth SR, Law CJ (2013) Multidrug resistance protein MdtM adds to the repertoire of antiporters involved in alkaline pH homeostasis in Escherichia coli. BMC Microbiol 13:113. doi:10.1186/1471-2180-13-113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Paul S, Alegre KO, Holdsworth SR, Rice M, Brown JA, McVeigh P, Kelly SM, Law CJ (2014) A single-component multidrug transporter of the major facilitator superfamily is part of a network that protects Escherichia coli from bile salt stress. Mol Microbiol 92:872–884. doi:10.1111/mmi.12597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Liu J, Keelan P, Bennett PM, Enne VI (2009) Characterization of a novel macrolide efflux gene, mef(B), found linked to sul3 in porcine Escherichia coli. J Antimicrob Chemother 63:423–426. doi:10.1093/jac/dkn523

    Article  CAS  PubMed  Google Scholar 

  90. Cattoir V, Poirel L, Nordmann P (2008) Plasmid-mediated quinolone resistance pump QepA2 in an Escherichia coli isolate from France. Antimicrob Agents Chemother 52:3801–3804. doi:10.1128/AAC.00638-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Levy SB (1992) Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother 36:695–703. doi:10.1128/AAC.36.4.695

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kobayashi N, Nishino K, Yamaguchi A (2001) Novel macrolide-specific ABC-type efflux transporter in Escherichia coli. J Bacteriol 183:5639–5644. doi:10.1128/JB.183.19.5639-5644.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Yamanaka H, Kobayashi H, Takahashi E, Okamoto K (2008) MacAB is involved in the secretion of Escherichia coli heat-stable enterotoxin II. J Bacteriol 190:7693–7698. doi:10.1128/JB.00853-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Turlin E, Heuck G, Simoes Brandao MI, Szili N, Mellin JR, Lange N, Wandersman C (2014) Protoporphyrin (PPIX) efflux by the MacAB-TolC pump in Escherichia coli. Microbiol Open 3:849–859. doi:10.1002/mbo3.203

    Article  CAS  Google Scholar 

  95. Lu S, Zgurskaya HI (2013) MacA, a periplasmic membrane fusion protein of the macrolide transporter MacAB-TolC, binds lipopolysaccharide core specifically and with high affinity. J Bacteriol 195:4865–4872. doi:10.1128/JB.00756-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Solbiati JO, Ciaccio M, Farias RN, Salomon RA (1996) Genetic analysis of plasmid determinants for microcin J25 production and immunity. J Bacteriol 178:3661–3663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Delgado MA, Solbiati JO, Chiuchiolo MJ, Farias RN, Salomon RA (1999) Escherichia coli outer membrane protein TolC is involved in production of the peptide antibiotic microcin J25. J Bacteriol 181:1968–1970

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Choudhury HG, Tong Z, Mathavan I, Li Y, Iwata S, Zirah S, Rebuffat S, van Veen HW et al (2014) Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state. Proc Natl Acad Sci U S A 111:9145–9150. doi:10.1073/pnas.1320506111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Woebking B, Reuter G, Shilling RA, Velamakanni S, Shahi S, Venter H, Balakrishnan L, van Veen HW (2005) Drug-lipid A interactions on the Escherichia coli ABC transporter MsbA. J Bacteriol 187:6363–6369. doi:10.1128/JB.187.18.6363-6369.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Reuter G, Janvilisri T, Venter H, Shahi S, Balakrishnan L, van Veen HW (2003) The ATP binding cassette multidrug transporter LmrA and lipid transporter MsbA have overlapping substrate specificities. J Biol Chem 278:35193–35198. doi:10.1074/jbc.M306226200

    Article  CAS  PubMed  Google Scholar 

  101. Karow M, Georgopoulos C (1993) The essential Escherichia coli msbA gene, a multicopy suppressor of null mutations in the htrB gene, is related to the universally conserved family of ATP-dependent translocators. Mol Microbiol 7:69–79. doi:10.1111/j.1365-2958.1993.tb01098

    Article  CAS  PubMed  Google Scholar 

  102. Eckford PD, Sharom FJ (2008) Functional characterization of Escherichia coli MsbA: interaction with nucleotides and substrates. J Biol Chem 283:12840–12850. doi:10.1074/jbc.M708274200

    Article  CAS  PubMed  Google Scholar 

  103. Siarheyeva A, Sharom FJ (2009) The ABC transporter MsbA interacts with lipid A and amphipathic drugs at different sites. Biochem J 419:317–328. doi:10.1042/BJ20081364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Doshi R, van Veen HW (2013) Substrate binding stabilizes a pre-translocation intermediate in the ATP-binding cassette transport protein MsbA. J Biol Chem 288:21638–21647. doi:10.1074/jbc.M113.485714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Delgado MA, Vincent PA, Farias RN, Salomon RA (2005) YojI of Escherichia coli functions as a microcin J25 efflux pump. J Bacteriol 187:3465–3470. doi:10.1128/JB.187.10.3465-3470.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Socias SB, Vincent PA, Salomon RA (2008) The leucine-responsive regulatory protein, Lrp, modulates microcin J25 intrinsic resistance in Escherichia coli by regulating expression of the YojI microcin exporter. J Bacteriol 191:1343–1348. doi:10.1128/JB.01074-08

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Kumar S, Doerrler WT (2014) Members of the conserved DedA family are likely membrane transporters and are required for drug resistance in Escherichia coli. Antimicrob Agents Chemother 58:923–930. doi:10.1128/AAC.02238-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Thompkins K, Chattopadhyay B, Xiao Y, Henk MC, Doerrler WT (2008) Temperature sensitivity and cell division defects in an Escherichia coli strain with mutations in yghB and yqjA, encoding related and conserved inner membrane proteins. J Bacteriol 190:4489–4500. doi:10.1128/JB.00414-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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 42:1778–1782

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Yang S, Clayton SR, Zechiedrich EL (2003) Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli. J Antimicrob Chemother 51:545–556. doi:10.1093/jac/dkg126

    Article  CAS  PubMed  Google Scholar 

  111. Long F, Rouquette-Loughlin C, Shafer WM, Yu EW (2008) Functional cloning and characterization of the multidrug efflux pumps NorM from Neisseria gonorrhoeae and YdhE from Escherichia coli. Antimicrob Agents Chemother 52:3052–3060. doi:10.1128/AAC.00475-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Su XZ, 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. doi:10.1128/AAC.49.10.4362-4364.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Nichols RJ, Sen S, Choo YJ, Beltrao P, Zietek M, Chaba R, Lee S, Kazmierczak KM et al (2011) Phenotypic landscape of a bacterial cell. Cell 144:143–156. doi:10.1016/j.cell.2010.11.052

    Article  CAS  PubMed  Google Scholar 

  114. McAnulty MJ, Wood TK (2014) YeeO from Escherichia coli exports flavins. Bioengineered 5:386–392. doi:10.4161/21655979.2014.969173

    Article  PubMed  PubMed Central  Google Scholar 

  115. 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. doi:10.1128/JB.00666-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Beketskaia MS, Bay DC, Turner RJ (2014) Outer membrane protein OmpW participates with small multidrug resistance protein member EmrE in quaternary cationic compound efflux. J Bacteriol 196:1483–1414. doi:10.1128/JB.01483-14

    Article  CAS  Google Scholar 

  117. Schuldiner S (2009) EmrE, a model for studying evolution and mechanism of ion-coupled transporters. Biochim Biophys Acta 1794:748–762. doi:10.1016/j.bbapap.2008.12.018

    Article  CAS  PubMed  Google Scholar 

  118. Higashi K, Ishigure H, Demizu R, Uemura T, Nishino K, Yamaguchi A, Kashiwagi K, Igarashi K (2008) Identification of a spermidine excretion protein complex (MdtJI) in Escherichia coli. J Bacteriol 190:872–878. doi:10.1128/JB.01505-07

    Article  CAS  PubMed  Google Scholar 

  119. Chung YJ, Saier MH Jr (2002) Overexpression of the Escherichia coli sugE gene confers resistance to a narrow range of quaternary ammonium compounds. J Bacteriol 184:2543–2545. doi:10.1128/JB.184.9.2543-2545.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sarkar SK, Bhattacharyya A, Mandal SM (2015) YnfA, a SMR family efflux pump is abundant in Escherichia coli isolates from urinary infection. Indian J Med Microbiol 33:139–142. doi:10.4103/0255-0857.148415

    Google Scholar 

  121. Turner RJ, Taylor DE, Weiner JH (1997) Expression of Escherichia coli TehA gives resistance to antiseptics and disinfectants similar to that conferred by multidrug resistance efflux pumps. Antimicrob Agents Chemother 41:440–444

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Blattner FR, Plunkett G 3rd, Bloch CA, Perna NT, Burland V, Riley M, Collado-Vides J, Glasner JD et al (1997) The complete genome sequence of Escherichia coli K-12. Science 277:1453–1474. doi:10.1126/science.277.5331.1453

    Article  CAS  PubMed  Google Scholar 

  123. Mazzariol A, Cornaglia G, Nikaido H (2000) Contributions of the AmpC β-lactamase and the AcrAB multidrug efflux system in intrinsic resistance of Escherichia coli K-12 to β-lactams. Antimicrob Agents Chemother 44:1387–1390. doi:10.1128/AAC.44.5.1387-1390.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Opperman TJ, Kwasny SM, Kim HS, Nguyen ST, Houseweart C, D’Souza S, Walker GC, Peet NP et al (2014) Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrob Agents Chemother 58:722–733. doi:10.1128/AAC.01866-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Tseng TT, Gratwick KS, Kollman J, Park D, Nies DH, Goffeau A, Saier MH Jr (1999) The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins. J Mol Microbiol Biotechnol 1:107–125. doi:10.1007/s13205-013-0155-z

    CAS  PubMed  Google Scholar 

  126. 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. doi:10.1128/CMR.00117-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Koronakis V, Sharff A, Koronakis E, Luisi B, Hughes C (2000) Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature 405:914–919. doi:10.1038/35016007

    Article  CAS  PubMed  Google Scholar 

  128. Sharff A, Fanutti C, Shi J, Calladine C, Luisi B (2001) The role of the TolC family in protein transport and multidrug efflux. From stereochemical certainty to mechanistic hypothesis. Eur J Biochem 268:5011–5026. doi:10.1046/j.0014-2956.2001.02442.x

    Article  CAS  PubMed  Google Scholar 

  129. Elkins CA, Nikaido H (2002) Substrate specificity of the RND-type multidrug efflux pumps AcrB and AcrD of Escherichia coli is determined predominantly by two large periplasmic loops. J Bacteriol 184:6490–6498. doi:10.1128/JB.184.23.6490-6499.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Nikaido H (1996) Multidrug efflux pumps of Gram-negative bacteria. J Bacteriol 178:5853–5859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hayashi K, Ryosuke N, Sakurai K, Kitagawa K, Yamasaki S, Nishino K, Yamaguchi A (2016) AcrB-AcrA fusion proteins that act as multidrug efflux transporters. J Bacteriol 198:332–342. doi:10.1128/JB.00587-15

    Article  CAS  Google Scholar 

  132. Hobbs EC, Yin X, Paul BJ, Astarita JL, Storz G (2012) Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance. Proc Natl Acad Sci U S A 109:16696–16701. doi:10.1073/pnas.1210093109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ma D, Cook DN, Alberti M, Pon NG, Nikaido H, Hearst JE (1995) Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli. Mol Microbiol 16:45–55. doi:10.1111/j.1365-2958.1995.tb02390.x

    Article  CAS  PubMed  Google Scholar 

  134. Keeney D, Ruzin A, McAleese F, Murphy E, Bradford PA (2008) MarA-mediated overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Escherichia coli. J Antimicrob Chemother 61:46–53. doi:10.1093/jac/dkm397

    Article  CAS  PubMed  Google Scholar 

  135. Stubbings W, Bostock J, Ingham E, Chopra I (2005) Deletion of the multiple-drug efflux pump AcrAB in Escherichia coli prolongs the postantibiotic effect. Antimicrob Agents Chemother 49:1206–1208. doi:10.1128/AAC.49.3.1206-1208.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mazzariol A, Tokue Y, Kanegawa TM, Cornaglia G, Nikaido H (2000) High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA. Antimicrob Agents Chemother 44:3441–3443. doi:10.1128/AAC.44.12.3441-3443.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Webber MA, Piddock LJ (2001) Absence of mutations in marRAB or soxRS in acrB-overexpressing fluoroquinolone-resistant clinical and veterinary isolates of Escherichia coli. Antimicrob Agents Chemother 45:1550–1552. doi:10.1128/AAC.45.5.1550-1552.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sato T, Yokota S, Ichihashi R, Miyauchi T, Okubo T, Usui M, Fujii N, Tamura Y (2014) Isolation of Escherichia coli strains with AcrAB-TolC efflux pump-associated intermediate interpretation or resistance to fluoroquinolone, chloramphenicol and aminopenicillin from dogs admitted to a university veterinary hospital. J Vet Med Sci 76:937–945. doi:10.1292/jvms.13-0144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Aly SA, Boothe DM, Suh SJ (2015) A novel alanine to serine substitution mutation in SoxS induces overexpression of efflux pumps and contributes to multidrug resistance in clinical Escherichia coli isolates. J Antimicrob Chemother 70:2228–2233. doi:10.1093/jac/dkv105

    Article  CAS  PubMed  Google Scholar 

  140. Zayed AA, Essam TM, Hashem AG, El-Tayeb OM (2015) ‘Supermutators’ found amongst highly levofloxacin-resistant E. coli isolates: a rapid protocol for the detection of mutation sites. Emerg Microbes Infect 4:e4. doi:10.1038/emi.2015.4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Nishino K, Yamada J, Hirakawa H, Hirata T, Yamaguchi A (2003) Roles of TolC-dependent multidrug transporters of Escherichia coli in resistance to β-lactams. Antimicrob Agents Chemother 47:3030–3033. doi:10.1128/AAC.47.9.3030-3033.2003

    Google Scholar 

  142. Kobayashi N, Tamura N, van Veen HW, Yamaguchi A, Murakami S (2014) β-Lactam selectivity of multidrug transporters AcrB and AcrD resides in the proximal binding pocket. J Biol Chem 289:10680–10690. doi:10.1074/jbc.M114.547794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Klein JR, Henrich B, Plapp R (1991) Molecular analysis and nucleotide sequence of the envCD operon of Escherichia coli. Mol Gen Genet 230:230–240. doi:10.1007/BF00290673

    Article  CAS  PubMed  Google Scholar 

  144. Olliver A, Valle M, Chaslus-Dancla E, Cloeckaert A (2005) Overexpression of the multidrug efflux operon acrEF by insertional activation with IS1 or IS10 elements in Salmonella enterica serovar Typhimurium DT204 acrB mutants selected with fluoroquinolones. Antimicrob Agents Chemother 49:289–301. doi:10.1128/AAC.49.1.289-301.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hirakawa H, Takumi-Kobayashi A, Theisen U, Hirata T, Nishino K, Yamaguchi A (2008) AcrS/EnvR represses expression of the acrAB multidrug efflux genes in Escherichia coli. J Bacteriol 190:6276–6279. doi:10.1128/JB.00190-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Pletzer D, Weingart H (2014) Characterization and regulation of the resistance-nodulation-cell division-type multidrug efflux pumps MdtABC and MdtUVW from the fire blight pathogen Erwinia amylovora. BMC Microbiol 14:185. doi:10.1186/1471-2180-14-185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Kim HS, Nagore D, Nikaido H (2010) Multidrug efflux pump MdtBC of Escherichia coli is active only as a B2C heterotrimer. J Bacteriol 192:1377–1386. doi:10.1128/JB.01448-09

    Article  CAS  PubMed  Google Scholar 

  148. Kim HS, Nikaido H (2012) Different functions of MdtB and MdtC subunits in the heterotrimeric efflux transporter MdtB2C complex of Escherichia coli. Biochemistry 51:4188–4197. doi:10.1021/bi300379y

    Article  CAS  PubMed  Google Scholar 

  149. Zoetendal EG, Smith AH, Sundset MA, Mackie RI (2008) The BaeSR two-component regulatory system mediates resistance to condensed tannins in Escherichia coli. Appl Environ Microbiol 74:535–539. doi:10.1128/AEM.02271-07

    Article  CAS  PubMed  Google Scholar 

  150. Nishino K, Nikaido E, Yamaguchi A (2007) Regulation of multidrug efflux systems involved in multidrug and metal resistance of Salmonella enterica serovar Typhimurium. J Bacteriol 189:9066–9075. doi:10.1128/JB.01045-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Yamamoto K, Ishihama A (2005) Transcriptional response of Escherichia coli to external copper. Mol Microbiol 56:215–227. doi:10.1111/j.1365-2958.2005.04532.x

    Article  CAS  PubMed  Google Scholar 

  152. Kittleson JT, Loftin IR, Hausrath AC, Engelhardt KP, Rensing C, McEvoy MM (2006) Periplasmic metal-resistance protein CusF exhibits high affinity and specificity for both CuI and AgI. Biochemistry 45:11096–11102. doi:10.1021/bi0612622

    Article  CAS  PubMed  Google Scholar 

  153. Loftin IR, Franke S, Blackburn NJ, McEvoy MM (2007) Unusual Cu(I)/Ag(I) coordination of Escherichia coli CusF as revealed by atomic resolution crystallography and X-ray absorption spectroscopy. Protein Sci 16:2287–2293. doi:10.1110/ps.073021307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Gupta A, Matsui K, Lo JF, Silver S (1999) Molecular basis for resistance to silver cations in Salmonella. Nat Med 5:183–188. doi:10.1038/5545

    Article  CAS  PubMed  Google Scholar 

  155. Deng H, Si H-B, Zeng S-Y, Sun J, Fang L-X, Yang R-S, Liu Y-H, Liao X-P (2015) Prevalence of extended-spectrum cephalosporin-resistant Escherichia coli in a farrowing farm: ST1121 clone harboring IncHI2 plasmid contributes to the dissemination of bla CMY-2 . Front Microbiol 6:1210. doi:10.3389/fmicb.2015.01210

    PubMed  PubMed Central  Google Scholar 

  156. Long F, Su CC, Lei HT, Bolla JR, Do SV, Yu EW (2012) Structure and mechanism of the tripartite CusCBA heavy-metal efflux complex. Philos Trans R Soc Lond B Biol Sci 367:1047–1058. doi:10.1098/rstb.2011.0203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Su CC, Long F, Zimmermann MT, Rajashankar KR, Jernigan RL, Yu EW (2011) Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli. Nature 470:558–562. doi:10.1038/nature09743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lei HT, Chou TH, Su CC, Bolla JR, Kumar N, Radhakrishnan A, Long F, Delmar JA et al (2014) Crystal structure of the open state of the Neisseria gonorrhoeae MtrE outer membrane channel. PLoS One 9:e97475. doi:10.1371/journal.pone.0097475

    Google Scholar 

  159. Chacón KN, Mealman TD, McEvoy MM, Blackburn NJ (2014) Tracking metal ions through a Cu/Ag efflux pump assigns the functional roles of the periplasmic proteins. Proc Natl Acad Sci U S A 111:15373–15378. doi:10.1073/pnas.1411475111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Norman A, Hansen LH, She Q, Sorensen SJ (2008) Nucleotide sequence of pOLA52: a conjugative IncX1 plasmid from Escherichia coli which enables biofilm formation and multidrug efflux. Plasmid 60:59–74. doi:10.1016/j.plasmid.2008.03.003

    Article  CAS  PubMed  Google Scholar 

  161. Zhao L, Zhang J, Zheng B, Wei Z, Shen P, Li S, Li L, Xiao Y (2015) Molecular epidemiology and genetic diversity of fluoroquinolone-resistant Escherichia coli isolates from patients with community-onset infections in 30 Chinese county hospitals. J Clin Microbiol 53:766–770. doi:10.1128/JCM.02594-14

    Article  PubMed  CAS  Google Scholar 

  162. Kim HB, Wang M, Park CH, Kim EC, Jacoby GA, Hooper DC (2009) oqxAB encoding a multidrug efflux pump in human clinical isolates of Enterobacteriaceae. Antimicrob Agents Chemother 53:3582–3584. doi:10.1128/AAC.01574-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Li L, Liao X, Yang Y, Sun J, Li L, Liu B, Yang S, Ma J et al (2013) Spread of oqxAB in Salmonella enterica serotype Typhimurium predominantly by IncHI2 plasmids. J Antimicrob Chemother 68:2263–2268. doi:10.1093/jac/dkt209

    CAS  PubMed  Google Scholar 

  164. Perez F, Rudin SD, Marshall SH, Coakley P, Chen L, Kreiswirth BN, Rather PN, Hujer AM et al (2013) OqxAB, a quinolone and olaquindox efflux pump, is widely distributed among multidrug-resistant Klebsiella pneumoniae isolates of human origin. Antimicrob Agents Chemother 57:4602–4603. doi:10.1128/AAC.00725-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yuan J, Xu X, Guo Q, Zhao X, Ye X, Guo Y, Wang M (2012) Prevalence of the oqxAB gene complex in Klebsiella pneumoniae and Escherichia coli clinical isolates. J Antimicrob Chemother 67:1655–1659. doi:10.1093/jac/dks086

    Article  CAS  PubMed  Google Scholar 

  166. Yang T, Zeng Z, Rao L, Chen X, He D, Lv L, Wang J, Zeng L et al (2014) The association between occurrence of plasmid-mediated quinolone resistance and ciprofloxacin resistance in Escherichia coli isolates of different origins. Vet Microbiol 170:89–96. doi:10.1016/j.vetmic.2014.01.019

    Article  CAS  PubMed  Google Scholar 

  167. Chen X, Zhang W, Pan W, Yin J, Pan Z, Gao S, Jiao X (2012) Prevalence of qnr, aac(6′)-Ib-cr, qepA, and oqxAB in Escherichia coli isolates from humans, animals, and the environment. Antimicrob Agents Chemother 56:3423–3427. doi:10.1128/AAC.06191-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Li L, Liao XP, Liu ZZ, Huang T, Li X, Sun J, Liu BT, Zhang Q et al (2014) Co-spread of oqxAB and bla CTX-M-9G in non-Typhi Salmonella enterica isolates mediated by ST2-IncHI2 plasmids. Int J Antimicrob Agents 44:263–268. doi:10.1016/j.ijantimicag.2014.05.014

    Article  CAS  PubMed  Google Scholar 

  169. Chandran SP, Diwan V, Tamhankar AJ, Joseph BV, Rosales-Klintz S, Mundayoor S, Lundborg CS, Macaden R (2014) Detection of carbapenem resistance genes and cephalosporin, and quinolone resistance genes along with oqxAB gene in Escherichia coli in hospital wastewater: a matter of concern. J Appl Microbiol 117:984–995. doi:10.1111/jam.12591

    Article  CAS  PubMed  Google Scholar 

  170. Xu X, Cui S, Zhang F, Luo Y, Gu Y, Yang B, Li F, Chen Q et al (2014) Prevalence and characterization of cefotaxime and ciprofloxacin co-resistant Escherichia coli isolates in retail chicken carcasses and ground pork, China. Microb Drug Resist 20:73–81. doi:10.1089/mdr.2012.0224

    Article  CAS  PubMed  Google Scholar 

  171. Dotto G, Giacomelli M, Grilli G, Ferrazzi V, Carattoli A, Fortini D, Piccirillo A (2014) High prevalence of oqxAB in Escherichia coli isolates from domestic and wild lagomorphs in Italy. Microb Drug Resist 20:118–123. doi:10.1089/mdr.2013.0141

    Article  CAS  PubMed  Google Scholar 

  172. Liu BT, Wang XM, Liao XP, Sun J, Zhu HQ, Chen XY, Liu YH (2011) Plasmid-mediated quinolone resistance determinants oqxAB and aac(6′)-Ib-cr and extended-spectrum β-lactamase gene bla CTX-M-24 co-located on the same plasmid in one Escherichia coli strain from China. J Antimicrob Chemother 66:1638–1639. doi:10.1093/jac/dkr172

    Article  CAS  PubMed  Google Scholar 

  173. Wong MH, Yan M, Chan EW, Biao K, Chen S (2014) Emergence of clinical Salmonella enterica serovar Typhimurium isolates with concurrent resistance to ciprofloxacin, ceftriaxone, and azithromycin. Antimicrob Agents Chemother 58:3752–3756. doi:10.1128/AAC.02770-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Wong MH, Chan EW, Chen S (2015) Evolution and dissemination of OqxAB-like efflux pumps, an emerging quinolone resistance determinant among members of Enterobacteriaceae. Antimicrob Agents Chemother 59:3290–3297. doi:10.1128/AAC.00310-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lee A, Mao W, Warren MS, Mistry A, Hoshino K, Okumura R, Ishida H, Lomovskaya O (2000) Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance. J Bacteriol 182:3142–3150. doi:10.1128/JB.182.11.3142-3150.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Tal N, Schuldiner S (2009) A coordinated network of transporters with overlapping specificities provides a robust survival strategy. Proc Natl Acad Sci U S A 106:9051–9056. doi:10.1073/pnas.0902400106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Krizsan A, Knappe D, Hoffmann R (2015) Influence of the yjiL-mdtM gene cluster on the antibacterial activity of proline-rich antimicrobial peptides overcoming Escherichia coli resistance induced by the missing SbmA transporter system. Antimicrob Agents Chemother 59:5992–5998. doi:10.1128/AAC.01307-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Wang D, Hu E, Chen J, Tao X, Gutierrez K, Qi Y (2013) Characterization of novel ybjG and dacC variants in Escherichia coli. J Med Microbiol 62:1728–1734. doi:10.1099/jmm.0.062893-0

    Article  CAS  PubMed  Google Scholar 

  179. Wang D, Liang H, Chen J, Mou Y, Qi Y (2014) Structural and environmental features of novel mdfA variant and mdfA genes in recombinant regions of Escherichia coli. Microb Drug Resist 20:392–398. doi:10.1089/mdr.2013.0201

    Article  CAS  PubMed  Google Scholar 

  180. Yasufuku T, Shigemura K, Shirakawa T, Matsumoto M, Nakano Y, Tanaka K, Arakawa S, Kinoshita S et al (2011) Correlation of overexpression of efflux pump genes with antibiotic resistance in Escherichia coli strains clinically isolated from urinary tract infection patients. J Clin Microbiol 49:189–194. doi:10.1128/JCM.00827-10

    Article  CAS  PubMed  Google Scholar 

  181. Kim JY, Jeon SM, Kim H, Park MS, Kim SH (2011) A contribution of MdfA to resistance to fluoroquinolones in Shigella flexneri. Osong Public Health Res Perspect 2:216–217. doi:10.1016/j.phrp.2011.11.049

    Article  PubMed  PubMed Central  Google Scholar 

  182. Tirosh O, Sigal N, Gelman A, Sahar N, Fluman N, Siemion S, Bibi E (2012) Manipulating the drug/proton antiport stoichiometry of the secondary multidrug transporter MdfA. Proc Natl Acad Sci U S A 109:12473–12478. doi:10.1073/pnas.1203632109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Fluman N, Adler J, Rotenberg SA, Brown MH, Bibi E (2014) Export of a single drug molecule in two transport cycles by a multidrug efflux pump. Nat Commun 5:4615. doi:10.1038/ncomms5615

    Article  CAS  PubMed  Google Scholar 

  184. Arcangioli MA, Leroy-Setrin S, Martel JL, Chaslus-Dancla E (1999) A new chloramphenicol and florfenicol resistance gene flanked by two integron structures in Salmonella typhimurium DT104. FEMS Microbiol Lett 174:327–332. doi:10.1111/j.1574-6968.1999.tb13586.x

    Article  CAS  PubMed  Google Scholar 

  185. Meunier D, Jouy E, Lazizzera C, Doublet B, Kobisch M, Cloeckaert A, Madec JY (2010) Plasmid-borne florfenicol and ceftiofur resistance encoded by the floR and bla CMY-2 genes in Escherichia coli isolates from diseased cattle in France. J Med Microbiol 59:467–471. doi:10.1099/jmm.0.016162-0

    Article  CAS  PubMed  Google Scholar 

  186. Du X, Xia C, Shen J, Wu B, Shen Z (2004) Characterization of florfenicol resistance among calf pathogenic Escherichia coli. FEMS Microbiol Lett 236:183–189. doi:10.1111/j.1574-6968.2004.tb09645.x

    Article  CAS  PubMed  Google Scholar 

  187. Doublet B, Schwarz S, Kehrenberg C, Cloeckaert A (2005) Florfenicol resistance gene floR is part of a novel transposon. Antimicrob Agents Chemother 49:2106–2108. doi:10.1128/AAC.49.5.2106-2108.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Kadlec K, Kehrenberg C, Schwarz S (2007) Efflux-mediated resistance to florfenicol and/or chloramphenicol in Bordetella bronchiseptica: identification of a novel chloramphenicol exporter. J Antimicrob Chemother 59:191–196. doi:10.1093/jac/dkl498

    Article  CAS  PubMed  Google Scholar 

  189. Ahmed AM, Shimamoto T (2015) Molecular analysis of multidrug resistance in Shiga toxin-producing Escherichia coli O157:H7 isolated from meat and dairy products. Int J Food Microbiol 193:68–73. doi:10.1016/j.ijfoodmicro.2014.10.014

    Article  CAS  PubMed  Google Scholar 

  190. Liu BT, Li L, Fang LX, Sun J, Liao XP, Yang QE, Huang T, Liu YH (2014) Characterization of plasmids carrying oqxAB in bla CTX-M -negative Escherichia coli isolates from food-producing animals. Microb Drug Resist 20:641–650. doi:10.1089/mdr.2014.0022

    Article  CAS  PubMed  Google Scholar 

  191. Perichon B, Courvalin P, Galimand M (2007) Transferable resistance to aminoglycosides by methylation of G1405 in 16S rRNA and to hydrophilic fluoroquinolones by QepA-mediated efflux in Escherichia coli. Antimicrob Agents Chemother 51:2464–2469. doi:10.1128/AAC.00143-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Perichon B, Bogaerts P, Lambert T, Frangeul L, Courvalin P, Galimand M (2008) Sequence of conjugative plasmid pIP1206 mediating resistance to aminoglycosides by 16S rRNA methylation and to hydrophilic fluoroquinolones by efflux. Antimicrob Agents Chemother 52:2581–2592. doi:10.1128/AAC.01540-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Yamane K, Wachino J, Suzuki S, Kimura K, Shibata N, Kato H, Shibayama K, Konda T et al (2007) New plasmid-mediated fluoroquinolone efflux pump, QepA, found in an Escherichia coli clinical isolate. Antimicrob Agents Chemother 51:3354–3360. doi:10.1128/AAC.00339-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Kim HB, Park CH, Kim CJ, Kim EC, Jacoby GA, Hooper DC (2008) Prevalence of plasmid-mediated quinolone resistance determinants over a nine-year period. Antimicrob Agents Chemother 53:639–645. doi:10.1128/AAC.01051-08

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Yano H, Uemura M, Endo S, Kanamori H, Inomata S, Kakuta R, Ichimura S, Ogawa M et al (2013) Molecular characteristics of extended-spectrum β-lactamases in clinical isolates from Escherichia coli at a Japanese tertiary hospital. PLoS One 8:e64359. doi:10.1371/journal.pone.0064359

    Google Scholar 

  196. Rincon G, Radice M, Giovanakis M, Di Conza JA, Gutkind G (2014) First report of plasmid-mediated fluoroquinolone efflux pump QepA in Escherichia coli clinical isolate ST68, in South America. Diagn Microbiol Infect Dis 79:70–72. doi:10.1016/j.diagmicrobio.2014.01.007

    Article  CAS  PubMed  Google Scholar 

  197. Varela AR, Macedo GN, Nunes OC, Manaia CM (2015) Genetic characterization of fluoroquinolone resistant Escherichia coli from urban streams and municipal and hospital effluents. FEMS Microbiol Ecol 91. doi:10.1093/femsec/fiv015

  198. Yamane K, Wachino J, Suzuki S, Arakawa Y (2008) Plasmid-mediated qepA gene among Escherichia coli clinical isolates from Japan. Antimicrob Agents Chemother 52:1564–1566. doi:10.1128/AAC.01137-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Liu JH, Deng YT, Zeng ZL, Gao JH, Chen L, Arakawa Y, Chen ZL (2008) Coprevalence of plasmid-mediated quinolone resistance determinants QepA, Qnr, and AAC(6′)-Ib-cr among 16S rRNA methylase RmtB-producing Escherichia coli isolates from pigs. Antimicrob Agents Chemother 52:2992–2993. doi:10.1128/AAC.01686-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Machuca J, Briales A, Diaz-de-Alba P, Martinez-Martinez L, Pascual A, Rodriguez-Martinez JM (2015) Effect of the efflux pump QepA2 combined with chromosomally mediated mechanisms on quinolone resistance and bacterial fitness in Escherichia coli. J Antimicrob Chemother 70:2524–2527. doi:10.1093/jac/dkv144

    Article  CAS  PubMed  Google Scholar 

  201. Chopra I, Roberts M (2001) Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiol Mol Biol Rev 65:232–260. doi:10.1128/MMBR.65.2.232-260.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Roberts MC (2005) Update on acquired tetracycline resistance genes. FEMS Microbiol Lett 245:195–203. doi:10.1016/j.femsle.2005.02.034

    Article  CAS  PubMed  Google Scholar 

  203. Mendez B, Tachibana C, Levy SB (1980) Heterogeneity of tetracycline resistance determinants. Plasmid 3:99–108. doi:10.1016/0147-619X(80)90101-8

    Article  CAS  PubMed  Google Scholar 

  204. US Department of Agriculture (2013) National antimicrobial resistance monitoring system. 2011 annual animal report, Athens, GA, USA

    Google Scholar 

  205. Curiale MS, Levy SB (1982) Two complementation groups mediate tetracycline resistance determined by Tn10. J Bacteriol 151:209–215

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Tuckman M, Petersen PJ, Projan SJ (2000) Mutations in the interdomain loop region of the tetA(A) tetracycline resistance gene increase efflux of minocycline and glycylcyclines. Microb Drug Resist 6:277–282. doi:10.1089/mdr.2000.6.277

    Article  CAS  PubMed  Google Scholar 

  207. Guay GG, Tuckman M, Rothstein DM (1994) Mutations in the tetA(B) gene that cause a change in substrate specificity of the tetracycline efflux pump. Antimicrob Agents Chemother 38:857–860. doi:10.1128/AAC.38.4.857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Sapunaric FM, Levy SB (2005) Substitutions in the interdomain loop of the Tn10 TetA efflux transporter alter tetracycline resistance and substrate specificity. Microbiology 151:2315–2322. doi:10.1099/mic.0.27997-0

    Article  CAS  PubMed  Google Scholar 

  209. Tikhonova EB, Devroy VK, Lau SY, Zgurskaya HI (2007) Reconstitution of the Escherichia coli macrolide transporter: the periplasmic membrane fusion protein MacA stimulates the ATPase activity of MacB. Mol Microbiol 63:895–910. doi:10.1111/j.1365-2958.2006.05549.x

    Article  CAS  PubMed  Google Scholar 

  210. Lu S, Zgurskaya HI (2012) Role of ATP binding and hydrolysis in assembly of MacAB-TolC macrolide transporter. Mol Microbiol 86:1132–1143. doi:10.1111/mmi.12046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Reyes CL, Ward A, Yu J, Chang G (2006) The structures of MsbA: insight into ABC transporter-mediated multidrug efflux. FEBS Lett 580:1042–1048. doi:10.1016/j.febslet.2005.11.033

    Article  CAS  PubMed  Google Scholar 

  212. Borbat PP, Surendhran K, Bortolus M, Zou P, Freed JH, McHaourab HS (2007) Conformational motion of the ABC transporter MsbA induced by ATP hydrolysis. PLoS Biol 5:e271. doi:10.1371/journal.pbio.0050271

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Ward A, Reyes CL, Yu J, Roth CB, Chang G (2007) Flexibility in the ABC transporter MsbA: alternating access with a twist. Proc Natl Acad Sci U S A 104:19005–19010. doi:10.1073/pnas.0709388104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Doshi R, Ali A, Shi W, Freeman EV, Fagg LA, van Veen HW (2013) Molecular disruption of the power stroke in the ATP-binding cassette transport protein MsbA. J Biol Chem 288:6801–6813. doi:10.1074/jbc.M112.430074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Kim JY, Jeon SM, Kim H, Lim N, Park MS, Kim SH (2012) Resistance to fluoroquinolone by a combination of efflux and target site mutations in enteroaggregative Escherichia coli isolated in Korea. Osong Public Health Res Perspect 3:239–244. doi:10.1016/j.phrp.2012.11.002

    Article  PubMed  PubMed Central  Google Scholar 

  216. Yang S, Lopez CR, Zechiedrich EL (2006) Quorum sensing and multidrug transporters in Escherichia coli. Proc Natl Acad Sci U S A 103:2386–2391. doi:10.1073/pnas.0502890102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Shea JE, Hensel M, Gleeson C, Holden DW (1996) Identification of a virulence locus encoding a second type III secretion system in Salmonella typhimurium. Proc Natl Acad Sci U S A 93:2593–2597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Schuldiner S (2014) Competition as a way of life for H+-coupled antiporters. J Mol Biol 426:2539–2546. doi:10.1016/j.jmb.2014.05.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Zou L, Meng J, McDermott PF, Wang F, Yang Q, Cao G, Hoffmann M, Zhao S (2014) Presence of disinfectant resistance genes in Escherichia coli isolated from retail meats in the USA. J Antimicrob Chemother 69:2644–2649. doi:10.1093/jac/dku197

    Article  CAS  PubMed  Google Scholar 

  220. Guo L, Long M, Huang Y, Wu G, Deng W, Yang X, Li B, Meng Y et al (2015) Antimicrobial and disinfectant resistance of Escherichia coli isolated from giant pandas. J Appl Microbiol 119:59–64. doi:10.1111/jam.12820

    Article  CAS  Google Scholar 

  221. Sikora CW, Turner RJ (2005) SMR proteins SugE and EmrE bind ligand with similar affinity and stoichiometry. Biochem Biophys Res Commun 335:105–111. doi:10.1016/j.bbrc.2005.07.051

    Article  CAS  PubMed  Google Scholar 

  222. Militello KT, Mandarano AH, Varechtchouk O, Simon RD (2014) Cytosine DNA methylation influences drug resistance in Escherichia coli through increased sugE expression. FEMS Microbiol Lett 350:100–106. doi:10.1111/1574-6968.12299

    Article  CAS  PubMed  Google Scholar 

  223. Liu M, Turner RJ, Winstone TL, Saetre A, Dyllick-Brenzinger M, Jickling G, Tari LW, Weiner JH et al (2000) Escherichia coli TehB requires S-adenosylmethionine as a cofactor to mediate tellurite resistance. J Bacteriol 182:6509–6513. doi:10.1128/JB.182.22.6509-6513.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Pei B, Wang Y, Katzianer DS, Wang H, Wu H, Zhong Z, Zhu J (2013) Role of a TehA homolog in Vibrio cholerae C6706 antibiotic resistance and intestinal colonization. Can J Microbiol 59:136–139. doi:10.1139/cjm-2012-0673

    Article  CAS  PubMed  Google Scholar 

  225. Hirakawa H, Inazumi Y, Masaki T, Hirata T, Yamaguchi A (2005) Indole induces the expression of multidrug exporter genes in Escherichia coli. Mol Microbiol 55:1113–1126. doi:10.1111/j.1365-2958.2004.04449.x

    Article  CAS  PubMed  Google Scholar 

  226. Ma D, Alberti M, Lynch C, Nikaido H, Hearst JE (1996) The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals. Mol Microbiol 19:101–112. doi:10.1046/j.1365-2958.1996.357881.x

    Article  CAS  PubMed  Google Scholar 

  227. Li M, Gu R, Su CC, Routh MD, Harris KC, Jewell ES, McDermott G, Yu EW (2007) Crystal structure of the transcriptional regulator AcrR from Escherichia coli. J Mol Biol 374:591–603. doi:10.1016/j.jmb.2007.09.064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Su CC, Yu EW (2007) Ligand-transporter interaction in the AcrB multidrug efflux pump determined by fluorescence polarization assay. FEBS Lett 581:4972–4976. doi:10.1016/j.febslet.2007.09.035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Gu R, Li M, Su CC, Long F, Routh MD, Yang F, McDermott G, Yu EW (2008) Conformational change of the AcrR regulator reveals a possible mechanism of induction. Acta Crystallogr Sect F Struct Biol Cryst Commun 64:584–588. doi:10.1107/S1744309108016035

    Google Scholar 

  230. Rahmati S, Yang S, Davidson AL, Zechiedrich EL (2002) Control of the AcrAB multidrug efflux pump by quorum-sensing regulator SdiA. Mol Microbiol 43:677–685. doi:10.1046/j.1365-2958.2002.02773.x

    Article  CAS  PubMed  Google Scholar 

  231. Kim T, Duong T, Wu CA, Choi J, Lan N, Kang SW, Lokanath NK, Shin D et al (2014) Structural insights into the molecular mechanism of Escherichia coli SdiA, a quorum-sensing receptor. Acta Crystallogr D Biol Crystallogr 70:694–707. doi:10.1107/S1399004713032355

    Article  CAS  PubMed  Google Scholar 

  232. Martin RG, Rosner JL (2002) Genomics of the marA/soxS/rob regulon of Escherichia coli: identification of directly activated promoters by application of molecular genetics and informatics to microarray data. Mol Microbiol 44:1611–1624. doi:10.1046/j.1365-2958.2002.02985.x

    Article  CAS  PubMed  Google Scholar 

  233. Nikaido H, Rosenberg EY, Foulds J (1983) Porin channels in Escherichia coli: studies with β-lactams in intact cells. J Bacteriol 153:232–240

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Nicoloff H, Perreten V, Levy SB (2007) Increased genome instability in Escherichia coli lon mutants: relation to emergence of multiple-antibiotic-resistant (Mar) mutants caused by insertion sequence elements and large tandem genomic amplifications. Antimicrob Agents Chemother 51:1293–1303. doi:10.1128/AAC.01128-06

    Google Scholar 

  235. Alekshun MN, Levy SB (1997) Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob Agents Chemother 41:2067–2075

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Gallegos MT, Schleif R, Bairoch A, Hofmann K, Ramos JL (1997) Arac/XylS family of transcriptional regulators. Microbiol Mol Biol Rev 61:393–410

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Rhee S, Martin RG, Rosner JL, Davies DR (1998) A novel DNA-binding motif in MarA: the first structure for an AraC family transcriptional activator. Proc Natl Acad Sci U S A 95:10413–10418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Barbosa TM, Levy SB (2000) Differential expression of over 60 chromosomal genes in Escherichia coli by constitutive expression of MarA. J Bacteriol 182:3467–3474. doi:10.1128/JB.182.12.3467-3474.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Du D, Wang Z, James NR, Voss JE, Klimont E, Ohene-Agyei T, Venter H, Chiu W et al (2014) Structure of the AcrAB-TolC multidrug efflux pump. Nature 509:512–515. doi:10.1038/nature13205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF (2001) The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3Å resolution. Nat Struct Biol 8:710–714. doi:10.1038/90429

    Article  CAS  PubMed  Google Scholar 

  241. Griffith KL, Shah IM, Wolf RE Jr (2004) Proteolytic degradation of Escherichia coli transcription activators SoxS and MarA as the mechanism for reversing the induction of the superoxide (SoxRS) and multiple antibiotic resistance (Mar) regulons. Mol Microbiol 51:1801–1816. doi:10.1046/j.1365-2958.2003.03952.x

    Article  CAS  PubMed  Google Scholar 

  242. Ruiz C, Levy SB (2010) Many chromosomal genes modulate MarA-mediated multidrug resistance in Escherichia coli. Antimicrob Agents Chemother 54:2125–2134. doi:10.1128/AAC.01420-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. McMurry LM, Oethinger M, Levy SB (1998) Overexpression of marA, soxS, or acrAB produces resistance to triclosan in laboratory and clinical strains of Escherichia coli. FEMS Microbiol Lett 166:305–309. doi:10.1111/j.1574-6968.1998.tb13905.x

    Article  CAS  PubMed  Google Scholar 

  244. Oethinger M, Podglajen I, Kern WV, Levy SB (1998) Overexpression of the marA or soxS regulatory gene in clinical topoisomerase mutants of Escherichia coli. Antimicrob Agents Chemother 42:2089–2094

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Li X-Z, Nikaido H (2004) Efflux-mediated drug resistance in bacteria. Drugs 64:159–204. doi:10.2165/00003495-200464020-00004

    Article  CAS  PubMed  Google Scholar 

  246. Rosenberg EY, Bertenthal D, Nilles ML, Bertrand KP, Nikaido H (2003) Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with Rob regulatory protein. Mol Microbiol 48:1609–1619. doi:10.1046/j.1365-2958.2003.03531.x

    Article  CAS  PubMed  Google Scholar 

  247. Nishino K, Yamaguchi A (2002) EvgA of the two-component signal transduction system modulates production of the yhiUV multidrug transporter in Escherichia coli. J Bacteriol 184:2319–2323. doi:10.1128/JB.184.8.2319-2323.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Eguchi Y, Itou J, Yamane M, Demizu R, Yamato F, Okada A, Mori H, Kato A et al (2007) B1500, a small membrane protein, connects the two-component systems EvgS/EvgA and PhoQ/PhoP in Escherichia coli. Proc Natl Acad Sci U S A 104:18712–18717. doi:10.1073/pnas.0705768104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Zhang A, Rosner JL, Martin RG (2008) Transcriptional activation by MarA, SoxS and Rob of two tolC promoters using one binding site: a complex promoter configuration for tolC in Escherichia coli. Mol Microbiol 69:1450–1455. doi:10.1111/j.1365-2958.2008.06371.x

    Google Scholar 

  250. Parker A, Gottesman S (2014) Small RNA regulation of a multidrug efflux pump. FASEB J 28(1 Suppl):750.751

    Google Scholar 

  251. Parker A, Gottesman S (2016) Small RNA regulation of TolC, the outer membrane component of bacterial multidrug transporters. J Bacteriol 198:1101–1113. doi:10.1128/JB.00971-15

    Google Scholar 

  252. Yamada J, Yamasaki S, Hirakawa H, Hayashi-Nishino M, Yamaguchi A, Nishino K (2010) Impact of the RNA chaperone Hfq on multidrug resistance in Escherichia coli. J Antimicrob Chemother 65:853–858. doi:10.1093/jac/dkq067

    Article  CAS  PubMed  Google Scholar 

  253. Xu B, Li C, Zheng Y, Si S, Shi Y, Huang Y, Zhang J, Cui Y et al (2015) Simulated microgravity affects ciprofloxacin susceptibility and expression of acrAB-tolC genes in E. coli ATCC25922. Int J Clin Exp Pathol 8:7945–7952

    PubMed  PubMed Central  Google Scholar 

  254. Curiao T, Marchi E, Viti C, Oggioni MR, Baquero F, Martinez JL, Coque TM (2015) Polymorphic variation in susceptibility and metabolism of triclosan-resistant mutants of Escherichia coli and Klebsiella pneumoniae clinical strains obtained after exposure to biocides and antibiotics. Antimicrob Agents Chemother 59:3413–3423. doi:10.1128/AAC.00187-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Leblanc SK, Oates CW, Raivio TL (2011) Characterization of the induction and cellular role of the BaeSR two-component envelope stress response of Escherichia coli. J Bacteriol 193:3367–3375. doi:10.1128/JB.01534-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Raffa RG, Raivio TL (2002) A third envelope stress signal transduction pathway in Escherichia coli. Mol Microbiol 45:1599–1611. doi:10.1046/j.1365-2958.2002.03112.x

    Article  CAS  PubMed  Google Scholar 

  257. Rowley G, Spector M, Kormanec J, Roberts M (2006) Pushing the envelope: extracytoplasmic stress responses in bacterial pathogens. Nat Rev Microbiol 4:383–394. doi:10.1038/nrmicro1394

    Article  CAS  PubMed  Google Scholar 

  258. Price NL, Raivio TL (2009) Characterization of the Cpx regulon in Escherichia coli strain MC4100. J Bacteriol 191:1798–1815. doi:10.1128/JB.00798-08

    Article  CAS  PubMed  Google Scholar 

  259. Perez-Rodriguez R, Haitjema C, Huang Q, Nam KH, Bernardis S, Ke A, DeLisa MP (2011) Envelope stress is a trigger of CRISPR RNA-mediated DNA silencing in Escherichia coli. Mol Microbiol 79:584–599. doi:10.1111/j.1365-2958.2010.07482.x

    Article  CAS  PubMed  Google Scholar 

  260. Nishino K, Honda T, Yamaguchi A (2005) Genome-wide analyses of Escherichia coli gene expression responsive to the BaeSR two-component regulatory system. J Bacteriol 187:1763–1772. doi:10.1128/JB.187.5.1763-1772.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. De Wulf P, McGuire AM, Liu X, Lin EC (2002) Genome-wide profiling of promoter recognition by the two-component response regulator CpxR-P in Escherichia coli. J Biol Chem 277:26652–26661. doi:10.1074/jbc.M203487200

    Article  PubMed  CAS  Google Scholar 

  262. Otto K, Silhavy TJ (2002) Surface sensing and adhesion of Escherichia coli controlled by the Cpx-signaling pathway. Proc Natl Acad Sci U S A 99:2287–2292. doi:10.1073/pnas.042521699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Nishino K, Yamasaki S, Hayashi-Nishino M, Yamaguchi A (2010) Effect of NlpE overproduction on multidrug resistance in Escherichia coli. Antimicrob Agents Chemother 54:2239–2243. doi:10.1128/AAC.01677-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Cordeiro RP, Krause DO, Doria JH, Holley RA (2014) Role of the BaeSR two-component regulatory system in resistance of Escherichia coli O157:H7 to allyl isothiocyanate. Food Microbiol 42:136–141. doi:10.1016/j.fm.2014.03.011

    Article  CAS  PubMed  Google Scholar 

  265. Hu WS, Chen HW, Zhang RY, Huang CY, Shen CF (2011) The expression levels of outer membrane proteins STM1530 and OmpD, which are influenced by the CpxAR and BaeSR two-component systems, play important roles in the ceftriaxone resistance of Salmonella enterica serovar Typhimurium. Antimicrob Agents Chemother 55:3829–3837. doi:10.1128/AAC.00216-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Guerrero P, Collao B, Morales EH, Calderon IL, Ipinza F, Parra S, Saavedra CP, Gil F (2012) Characterization of the BaeSR two-component system from Salmonella Typhimurium and its role in ciprofloxacin-induced mdtA expression. Arch Microbiol 194:453–460. doi:10.1007/s00203-011-0779-5

    Article  CAS  PubMed  Google Scholar 

  267. Pletzer D, Stahl A, Oja AE, Weingart H (2015) Role of the cell envelope stress regulators BaeR and CpxR in control of RND-type multidrug efflux pumps and transcriptional cross talk with exopolysaccharide synthesis in Erwinia amylovora. Arch Microbiol 197:761–772. doi:10.1007/s00203-015-1109-0

    Article  CAS  PubMed  Google Scholar 

  268. Bleuel C, Grosse C, Taudte N, Scherer J, Wesenberg D, Krauss GJ, Nies DH, Grass G (2005) TolC is involved in enterobactin efflux across the outer membrane of Escherichia coli. J Bacteriol 187:6701–6707. doi:10.1128/JB.187.19.6701-6707.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Hirakawa H, Inazumi Y, Senda Y, Kobayashi A, Hirata T, Nishino K, Yamaguchi A (2006) N-acetyl-D-glucosamine induces the expression of multidrug exporter genes, mdtEF, via catabolite activation in Escherichia coli. J Bacteriol 188:5851–5858. doi:10.1128/JB.00301-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Nishino K, Senda Y, Yamaguchi A (2008) The AraC-family regulator GadX enhances multidrug resistance in Escherichia coli by activating expression of mdtEF multidrug efflux genes. J Infect Chemother 14:23–29. doi:10.1007/s10156-007-0575-y

    Article  CAS  PubMed  Google Scholar 

  271. Nishino K, Senda Y, Hayashi-Nishino M, Yamaguchi A (2009) Role of the AraC-XylS family regulator YdeO in multi-drug resistance of Escherichia coli. J Antibiot (Tokyo) 62:251–257. doi:10.1038/ja.2009.23

    Article  CAS  Google Scholar 

  272. Sledjeski D, Gottesman S (1995) A small RNA acts as an antisilencer of the H-NS-silenced rcsA gene of Escherichia coli. Proc Natl Acad Sci U S A 92:2003–2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Ravikumar S, Pham VD, Lee SH, Yoo IK, Hong SH (2012) Modification of CusSR bacterial two-component systems by the introduction of an inducible positive feedback loop. J Ind Microbiol Botechnol 39:861–868. doi:10.1007/s10295-012-1096-y

    Article  CAS  Google Scholar 

  274. Lomovskaya O, Lewis K, Matin A (1995) EmrR is a negative regulator of the Escherichia coli multidrug resistance pump EmrAB. J Bacteriol 177:2328–2334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Xiong A, Gottman A, Park C, Baetens M, Pandza S, Matin A (2000) The EmrR protein represses the Escherichia coli emrRAB multidrug resistance operon by directly binding to its promoter region. Antimicrob Agents Chemother 44:2905–2907. doi:10.1128/AAC.44.10.2905-2907.2000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Brooun A, Tomashek JJ, Lewis K (1999) Purification and ligand binding of EmrR, a regulator of a multidrug transporter. J Bacteriol 181:5131–5133

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Wu X, Altman R, Eiteman MA, Altman E (2014) Adaptation of Escherichia coli to elevated sodium concentrations increases cation tolerance and enables greater lactic acid production. Appl Environ Microbiol 80:2880–2888. doi:10.1128/AEM.03804-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  278. Sakamoto A, Terui Y, Yoshida T, Yamamoto T, Suzuki H, Yamamoto K, Ishihama A, Igarashi K et al (2015) Three members of polyamine modulon under oxidative stress conditions: two transcription factors (SoxR and EmrR) and a glutathione synthetic enzyme (GshA). PLoS One 10:e0124883. doi:10.1371/journal.pone.0124883

    Google Scholar 

  279. Grkovic S, Brown MH, Skurray RA (2002) Regulation of bacterial drug export systems. Microbiol Mol Biol Rev 66:671–701. doi:10.1128/MMBR.66.4.671-701.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Cuthbertson L, Nodwell JR (2013) The TetR family of regulators. Microbiol Mol Biol Rev 77:440–475. doi:10.1128/MMBR.00018-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Kobayashi A, Hirakawa H, Hirata T, Nishino K, Yamaguchi A (2006) Growth phase-dependent expression of drug exporters in Escherichia coli and its contribution to drug tolerance. J Bacteriol 188:5693–5703. doi:10.1128/JB.00217-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Leuzzi A, Di Martino ML, Campilongo R, Falconi M, Barbagallo M, Marcocci L, Pietrangeli P, Casalino M et al (2015) Multifactor regulation of the MdtJI polyamine transporter in Shigella. PLoS One 10:e0136744. doi:10.1371/journal.pone.0136744

    Google Scholar 

  283. Nikaido H (1998) The role of outer membrane and efflux pumps in the resistance of Gram-negative bacteria. Can we improve drug access? Drug Resist Updat 1:93–98. doi:10.1016/S1368-7646(98)80023-X

    Google Scholar 

  284. Nikaido H (2003) Molecular basis of bacterial outer membrane permeability revisited. Microbiol Mol Biol Rev 67:593–656. doi:10.1128/MMBR.67.4.593-656.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Vaara M (1993) Antibiotic-supersusceptible mutants of Escherichia coli and Salmonella typhimurium. Antimicrob Agents Chemother 37:2255–2260. doi:10.1128/AAC.37.11.2255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Harder KJ, Nikaido H, Matsuhashi M (1981) Mutants of Escherichia coli that are resistant to certain β-lactam compounds lack the OmpF porin. Antimicrob Agents Chemother 20:549–552. doi:10.1128/AAC.20.4.549

    Google Scholar 

  287. Nikaido H, Normark S (1987) Sensitivity of Escherichia coli to various β-lactams is determined by the interplay of outer membrane permeability and degradation by periplasmic β-lactamases: a quantitative predictive treatment. Mol Microbiol 1:29–36. doi:10.1111/j.1365-2958.1987.tb00523.x

    Google Scholar 

  288. Yethon JA, Whitfield C (2001) Purification and characterization of WaaP from Escherichia coli, a lipopolysaccharide kinase essential for outer membrane stability. J Biol Chem 276:5498–5504. doi:10.1074/jbc.M008255200

    Article  CAS  PubMed  Google Scholar 

  289. 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 96:7190–7195. doi:10.1073/pnas.96.13.7190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, Blais J, Cho D et al (2001) Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob Agents Chemother 45:105–116. doi:10.1128/AAC.45.1.105-116.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Murakami S, Tamura N, Saito A, Hirata T, Yamaguchi A (2004) Extramembrane central pore of multidrug exporter AcrB in Escherichia coli plays an important role in drug transport. J Biol Chem 279:3743–3748. doi:10.1074/jbc.M308893200

    Article  CAS  PubMed  Google Scholar 

  292. Bohnert JA, Karamian B, Nikaido H (2010) Optimized Nile red efflux assay of AcrAB-TolC multidrug efflux system shows competition between substrates. Antimicrob Agents Chemother 54:3770–3775. doi:10.1128/AAC.00620-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Nagano K, Nikaido H (2009) Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci U S A 106:5854–5858. doi:10.1073/pnas.0901695106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Lim SP, Nikaido H (2010) Kinetic parameters of efflux of penicillins by the multidrug efflux transporter AcrAB-TolC of Escherichia coli. Antimicrob Agents Chemother 54:1800–1806. doi:10.1128/AAC.01714-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. 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. doi:10.1073/pnas.1310333110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Kinana AD, Vargiu AV, Nikaido H (2013) Some ligands enhance the efflux of other ligands by the Escherichia coli multidrug pump AcrB. Biochemistry 52:8342–8351. doi:10.1021/bi401303v

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Kinana AD, Vargiu AV, May T, Nikaido H (2016) Aminoacyl β-naphthylamides as substrates and modulators of AcrB multidrug efflux pump. Proc Natl Acad Sci U S A 113:1405–1410. doi:10.1073/pnas.1525143113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Research in the Nikaido laboratory has been supported by a grant from the US Public Health Service (AI-09644). The views expressed in this chapter do not necessarily reflect those of Xian-Zhi Li’s affiliation, Health Canada.

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Authors and Affiliations

  1. Human Safety Division, Veterinary Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada

    Xian-Zhi Li

  2. Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA

    Hiroshi Nikaido

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  1. Xian-Zhi Li
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  2. Hiroshi Nikaido
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Correspondence to Xian-Zhi Li .

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Editors and Affiliations

  1. Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada

    Xian-Zhi Li

  2. U.S. Food and Drug Administration, Laurel, Maryland, USA

    Christopher A. Elkins

  3. University of Oklahoma, Norman, Oklahoma, USA

    Helen I. Zgurskaya

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Li, XZ., Nikaido, H. (2016). Antimicrobial Drug Efflux Pumps in Escherichia coli . In: Li, XZ., Elkins, C., Zgurskaya, H. (eds) Efflux-Mediated Antimicrobial Resistance in Bacteria. Adis, Cham. https://doi.org/10.1007/978-3-319-39658-3_9

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