The ins and outs of RND efflux pumps in Escherichia coli

Frontiers in Microbiology

Volumn 6, Issue JUN, 2015, Pages

  Anes, João ^a   McCusker, Matthew P ^a   Fanning, Séamus ^a   Martins, Marta ^a  

^a UNIVERSITY COLLEGE DUBLIN   (Ireland)

Author keywords

Antibiotics; Antimicrobial resistance; Biocides; Escherichia coli efflux pumps

Indexed keywords

ACRIFLAVINE; ANTIBIOTIC AGENT; ANTIINFECTIVE AGENT; BIOCIDE; HEAVY METAL;

ANTIBIOTIC RESISTANCE; BACTERIAL CELL; BACTERIAL PHENOMENA AND FUNCTIONS; CELL DIVISION; CELL MEMBRANE PERMEABILITY; COPPER TRANSPORTING EFFLUX SYSTEM; ESCHERICHIA COLI; HOSPITAL INFECTION; HUMAN; MULTIDRUG RESISTANCE; MULTIDRUG TRANSPORT EFFLUX SYSTEM; NONHUMAN; PROTEIN EXPRESSION; RESISTANCE NODULATION CELL DIVISION EFFLUX MECHANISM; REVIEW;

BACTERIA (MICROORGANISMS); ESCHERICHIA COLI; NEGIBACTERIA;

EID: 84936995991     PISSN: None     EISSN: 1664302X     Source Type: Journal    
DOI: 10.3389/fmicb.2015.00587     Document Type: Review

References (160)

1. Aires, J. R., and 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
2. Alvarez-Ortega, C., Olivares, J., and Martínez, J. L. (2013). RND multidrug efflux pumps: what are they good for? Front. Microbiol. 4:7. doi: 10.3389/fmicb.2013.00007
3. Amaral, L., Fanning, S., and Pagès, J.-M. (2011). Efflux pumps of gram-negative bacteria: genetic responses to stress and the modulation of their activity by pH, inhibitors, and phenothiazines. Adv. Enzymol. Relat. Areas Mol. Biol. 77, 61-108. doi: 10.1002/9780470920541.ch2
4. Amaral, L., and Molnar, J. (2012). Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis. Expert Rev. Anti. Infect. Ther. 10, 869-873. doi: 10.1586/eri.12.73
5. Andersson, D. I., and Hughes, D. (2014). Microbiological effects of sublethal levels of antibiotics. Nat. Rev. Microbiol. 12, 465-478. doi: 10.1038/nrmicro3270
6. Bagai, I., Liu, W., Rensing, C., Blackburn, N. J., and McEvoy, M. M. (2007). Substrate-linked conformational change in the periplasmic component of a Cu(I)/Ag(I) efflux system. J. Biol. Chem. 282, 35695-35702. doi: 10.1074/jbc.M703937200
7. Baranova, N., and 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
8. Bavro, V. N., Pietras, Z., Furnham, N., Pérez-Cano, L., Fernández-Recio, J., Pei, X. Y., et al. (2008). Assembly and channel opening in a bacterial drug efflux machine. Mol. Cell 30, 114-121. doi: 10.1016/j.molcel.2008.02.015
9. Beloin, C., Roux, A., and Ghigo, J. M. (2008). Escherichia coli biofilms. Curr. Top. Microbiol. Immunol. 322, 249-289. doi: 10.1007/978-3-540-75418-3_12
10. Bohnert, J. A., and Kern, W. V. (2005). Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob. Agents Chemother. 49, 849-852. doi: 10.1128/AAC.49.2.849-852.2005
11. Bohnert, J. A., Schuster, S., and Kern, W. V. (2013). Pimozide inhibits the AcrAB-TolC efflux pump in Escherichia coli. Open Microbiol. J. 7, 83-86. doi: 10.2174/1874285801307010083
12. Cagnacci, S., Gualco, L., Debbia, E., Schito, G. C., and Marchese, A. (2008). European emergence of ciprofloxacin-resistant Escherichia coli clonal groups O25:H4-ST 131 and O15:K52:H1 causing community-acquired uncomplicated cystitis. J. Clin. Microbiol. 46, 2605-2612. doi: 10.1128/JCM.00640-08
13. Capita, R., Riesco-Peláez, F., Alonso-Hernando, A., and Alonso-Calleja, C. (2014). Exposure of Escherichia coli ATCC 12806 to sublethal concentrations of food-grade biocides influences its ability to form biofilm, resistance to antimicrobials, and ultrastructure. Appl. Environ. Microbiol. 80, 1268-1280. doi: 10.1128/AEM.02283-13
14. Carraro, N., Matteau, D., Luo, P., Rodrigue, S., and Burrus, V. (2014). The master activator of IncA/C conjugative plasmids stimulates genomic islands and multidrug resistance dissemination. PLoS Genet. 10:e1004714. doi: 10.1371/journal.pgen.1004714
15. Castanon, J. I. R. (2007). History of the use of antibiotic as growth promoters in European poultry feeds Poult. Sci. 86, 2466-2471. doi: 10.3382/ps.2007-00249
16. Centers for Disease Control and Prevention (CDC). (2006). Ongoing multistate outbreak of Escherichia coli serotype O157:H7 infections associated with consumption of fresh spinach-United States, September 2006. MMWR. Morb. Mortal. Wkly. Rep. 55, 1045-1046.
17. Chacón, K. N., Mealman, T. D., McEvoy, M. M., and Blackburn, N. J. (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
18. Coldham, N. G., Webber, M., Woodward, M. J., and Piddock, L. J. V. (2010). A 96-well plate fluorescence assay for assessment of cellular permeability and active efflux in Salmonella enterica serovar Typhimurium and Escherichia coli. J. Antimicrob. Chemother. 65, 1655-1663. doi: 10.1093/jac/dkq169
19. Conroy, O., Kim, E.-H., McEvoy, M. M., and Rensing, C. (2010). Differing ability to transport nonmetal substrates by two RND-type metal exporters. FEMS Microbiol. Lett. 308, 115-122. doi: 10.1111/j.1574-6968.2010.02006.x
20. Coutinho, H. D. M., Costa, J. G. M., Lima, E. O., Falcão-Silva, V. S., and Siqueira-Júnior, J. P. (2010). Increasing of the aminoglicosyde antibiotic activity against a multidrug-resistant E. coli by Turnera ulmifolia L. and chlorpromazine. Biol. Res. Nurs. 11, 332-335. doi: 10.1177/1099800409340052
21. Delmar, J. A., Su, C.-C., and Yu, E. W. (2013). Structural mechanisms of heavy-metal extrusion by the Cus efflux system. Biometals 26, 593-607. doi: 10.1007/s10534-013-9628-0
22. Delmar, J. A., Su, C.-C., and Yu, E. W. (2014). Bacterial multidrug efflux transporters. Annu. Rev. Biophys. 43, 93-117. doi: 10.1146/annurev-biophys-051013-022855
23. Deng, Z., Shan, Y., Pan, Q., Gao, X., and 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
24. Du, D., Wang, Z., James, N. R., Voss, J. E., Klimont, E., Ohene-Agyei, T., et al. (2014). Structure of the AcrAB-TolC multidrug efflux pump. Nature 509, 512-515. doi: 10.1038/nature13205
25. Elkins, C. A., and Mullis, L. B. (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
26. Elkins, C. A., and 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
27. Elkins, C. A., and Nikaido, H. (2003). Chimeric analysis of AcrA function reveals the importance of its C-terminal domain in its interaction with the AcrB multidrug efflux pump. J. Bacteriol. 185, 5349-5356. doi: 10.1128/JB.185.18.5349-5356.2003
28. Fadli, M., Chevalier, J., Hassani, L., Mezrioui, N.-E., and Pagès, J.-M. (2014). Natural extracts stimulate membrane-associated mechanisms of resistance in Gram-negative bacteria. Lett. Appl. Microbiol. 58, 472-477. doi: 10.1111/lam.12216
29. Fernandez-Recio, J., Walas, F., Federici, L., Venkatesh Pratap, J., Bavro, V. N., Miguel, R. N., et al. (2004). A model of a transmembrane drug-efflux pump from Gram-negative bacteria. FEBS Lett. 578, 5-9. doi: 10.1016/j.febslet.2004.10.097
30. Fralick, J. A. (1996). Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli. J. Bacteriol. 178, 5803-5805.
31. Frawley, E. R., Crouch, M.-L. V., Bingham-Ramos, L. K., Robbins, H. F., Wang, W., Wright, G. D., et al. (2013). Iron and citrate export by a major facilitator superfamily pump regulates metabolism and stress resistance in Salmonella Typhimurium. Proc. Natl. Acad. Sci. U.S.A. 110, 12054-1209. doi: 10.1073/pnas.1218274110
32. Ge, Q., Yamada, Y., and Zgurskaya, H. (2009). The C-terminal domain of AcrA is essential for the assembly and function of the multidrug efflux pump AcrAB-TolC. J. Bacteriol. 191, 4365-4371. doi: 10.1128/JB.00204-09
33. Gilbert, P., and McBain, A. J. (2001). Biocide usage in the domestic setting and concern about antibacterial and antibiotic resistance. J. Infect. 43, 85-91. doi: 10.1053/jinf.2001.0853
34. Gillings, M. R. (2014). Integrons: past, present, and future. Microbiol. Mol. Biol. Rev. 78, 257-277. doi: 10.1128/MMBR.00056-13
35. Gudipaty, S. A., Larsen, A. S., Rensing, C., and McEvoy, M. M. (2012). Regulation of Cu(I)/Ag(I) efflux genes in Escherichia coli by the sensor kinase CusS. FEMS Microbiol. Lett. 330, 30-37. doi: 10.1111/j.1574-6968.2012.02529.x
36. Gunn, J. S. (2001). Bacterial modification of LPS and resistance to antimicrobial peptides. J. Endotoxin Res. 7, 57-62. doi: 10.1177/09680519010070011001
37. Hamner, S., McInnerney, K., Williamson, K., Franklin, M. J., and Ford, T. E. (2013). Bile salts affect expression of Escherichia coli O157:H7 genes for virulence and iron acquisition, and promote growth under iron limiting conditions. PLoS ONE 8:e74647. doi: 10.1371/journal.pone.0074647
38. Hassan, K. A., Elbourne, L. D. H., Li, L., Gamage, H. K. A. H., Liu, Q., Jackson, S. M., et al. (2015a). An ace up their sleeve: a transcriptomic approach exposes the AceI efflux protein of Acinetobacter baumannii and reveals the drug efflux potential hidden in many microbial pathogens. Front. Microbiol. 6:333. doi: 10.3389/fmicb.2015.00333
39. Hassan, K. A., Liu, Q., Henderson, P. J. F., and Paulsen, I. T. (2015b). Homologs of the Acinetobacter baumannii AceI transporter represent a new family of bacterial multidrug efflux systems. MBio 6, e01982-14. doi: 10.1128/mBio.01982-14
40. Higgins, M. K., Eswaran, J., Edwards, P., Schertler, G. F. X., Hughes, C., and Koronakis, V. (2004). Structure of the ligand-blocked periplasmic entrance of the bacterial multidrug efflux protein TolC. J. Mol. Biol. 342, 697-702. doi: 10.1016/j.jmb.2004.07.088
41. Hinchliffe, P., Symmons, M. F., Hughes, C., and Koronakis, V. (2013). Structure and operation of bacterial tripartite pumps. Annu. Rev. Microbiol. 67, 221-242. doi: 10.1146/annurev-micro-092412-155718
42. Hirakawa, H., Nishino, K., Yamada, J., Hirata, T., and Yamaguchi, A. (2003). Beta-lactam resistance modulated by the overexpression of response regulators of two-component signal transduction systems in Escherichia coli. J. Antimicrob. Chemother. 52, 576-582. doi: 10.1093/jac/dkg406
43. Hirakawa, H., Takumi-Kobayashi, A., Theisen, U., Hirata, T., Nishino, K., and 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
44. Hirata, T., Saito, A., Nishino, K., Tamura, N., and 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
45. Hobbs, E. C., Yin, X., Paul, B. J., Astarita, J. L., and 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
46. Horiyama, T., and 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
47. Husain, F., Bikhchandani, M., and Nikaido, H. (2011). Vestibules are part of the substrate path in the multidrug efflux transporter AcrB of Escherichia coli. J. Bacteriol. 193, 5847-5849. doi: 10.1128/JB.05759-11
48. Husain, F., and Nikaido, H. (2010). Substrate path in the AcrB multidrug efflux pump of Escherichia coli. Mol. Microbiol. 78, 320-330. doi: 10.1111/j.1365-2958.2010.07330.x
49. Ikonomidis, A., Tsakris, A., Kanellopoulou, M., Maniatis, A. N., and Pournaras, S. (2008). Effect of the proton motive force inhibitor carbonyl cyanide-m-chlorophenylhydrazone (CCCP) on Pseudomonas aeruginosa biofilm development. Lett. Appl. Microbiol. 47, 298-302. doi: 10.1111/j.1472-765X.2008.02430.x
50. Jellen-Ritter, A. S., and Kern, W. V. (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
51. Kern, W. V., Steinke, P., Schumacher, A., Schuster, S., von Baum, H., and Bohnert, J. A. (2006). Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Escherichia coli. J. Antimicrob. Chemother. 57, 339-343. doi: 10.1093/jac/dki445
52. Kim, E.-H., Nies, D. H., McEvoy, M. M., and Rensing, C. (2011). Switch or funnel: how RND-type transport systems control periplasmic metal homeostasis. J. Bacteriol. 193, 2381-2387. doi: 10.1128/JB.01323-10
53. Kim, H.-M., Xu, Y., Lee, M., Piao, S., Sim, S.-H., Ha, N.-C., et al. (2010a). Functional relationships between the AcrA hairpin tip region and the TolC aperture tip region for the formation of the bacterial tripartite efflux pump AcrAB-TolC. J. Bacteriol. 192, 4498-4503. doi: 10.1128/JB.00334-10
54. Kim, H.-S., Nagore, D., and Nikaido, H. (2010b). 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
55. Kim, H.-S., and Nikaido, H. (2012). Different functions of MdtB and MdtC subunits in the heterotrimeric efflux transporter MdtB(2)C complex of Escherichia coli. Biochemistry 51, 4188-4197. doi: 10.1021/bi300379y
56. Kim, J.-S., Jeong, H., Song, S., Kim, H.-Y., Lee, K., Hyun, J., et al. (2015). Structure of the tripartite multidrug efflux pump AcrAB-TolC suggests an alternative assembly mode. Mol. Cells 38, 180-186. doi: 10.14348/molcells.2015.2277
57. Kinana, A. D., Vargiu, A. V., and 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
58. Kobayashi, A., Hirakawa, H., Hirata, T., Nishino, K., and 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
59. Kobayashi, K., Tsukagoshi, N., and 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
60. Kobayashi, N., Tamura, N., van Veen, H. W., Yamaguchi, A., and Murakami, S. (2014). ß-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
61. Koronakis, V., Sharff, A., Koronakis, E., Luisi, B., and 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
62. Krishnamoorthy, G., Tikhonova, E. B., Dhamdhere, G., and Zgurskaya, H. I. (2013). On the role of TolC in multidrug efflux: the function and assembly of AcrAB-TolC tolerate significant depletion of intracellular TolC protein. Mol. Microbiol. 87, 982-997. doi: 10.1111/mmi.12143
63. Kulathila, R., Kulathila, R., Indic, M., and van den Berg, B. (2011). Crystal structure of Escherichia coli CusC, the outer membrane component of a heavy metal efflux pump. PLoS ONE 6:e15610. doi: 10.1371/journal.pone.0015610
64. Kvist, M., Hancock, V., and Klemm, P. (2008). Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl. Environ. Microbiol. 74, 7376-7382. doi: 10.1128/AEM.01310-08
65. Lamikanra, A., Crowe, J. L., Lijek, R. S., Odetoyin, B. W., Wain, J., Aboderin, A. O., et al. (2011). Rapid evolution of fluoroquinolone-resistant Escherichia coli in Nigeria is temporally associated with fluoroquinolone use. BMC Infect. Dis. 11:312. doi: 10.1186/1471-2334-11-312
66. Lau, S. Y., and Zgurskaya, H. I. (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
67. Lee, A., Mao, W., Warren, M. S., Mistry, A., Hoshino, K., Okumura, R., et al. (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
68. Lennen, R. M., Politz, M. G., Kruziki, M. A., and Pfleger, B. F. (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
69. Li, X.-Z., and Nikaido, H. (2009). Efflux-mediated drug resistance in bacteria: an update. Drugs 69, 1555-1623. doi: 10.2165/11317030-000000000-00000
70. Li, X.-Z., Plésiat, P., and 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
71. Lobedanz, S., Bokma, E., Symmons, M. F., Koronakis, E., Hughes, C., and Koronakis, V. (2007). A periplasmic coiled-coil interface underlying TolC recruitment and the assembly of bacterial drug efflux pumps. Proc. Natl. Acad. Sci. U.S.A. 104, 4612-4617. doi: 10.1073/pnas.0610160104
72. Loftin, I. R., Franke, S., Blackburn, N. J., and McEvoy, M. M. (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
73. Loftin, I. R., Franke, S., Roberts, S. A., Weichsel, A., Héroux, A., Montfort, W. R., et al. (2005). A novel copper-binding fold for the periplasmic copper resistance protein CusF. Biochemistry 44, 10533-10540. doi: 10.1021/bi050827b
74. Lomovskaya, O., Warren, M. S., Lee, A., Galazzo, J., Fronko, R., Lee, M., 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
75. Long, F., Su, C.-C., Lei, H.-T., Bolla, J. R., Do, S. V., and Yu, E. W. (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
76. Long, F., Su, C.-C., Zimmermann, M. T., Boyken, S. E., Rajashankar, K. R., Jernigan, R. L., et al. (2010). Crystal structures of the CusA efflux pump suggest methionine-mediated metal transport. Nature 467, 484-488. doi: 10.1038/nature09395
77. Lu, S., and Zgurskaya, H. I. (2012). Role of ATP binding and hydrolysis in assembly of MacAB-TolC macrolide transporter. Mol. Microbiol. 86, 1132-1143. doi: 10.1111/mmi.12046
78. Lubelski, J., Konings, W. N., and Driessen, A. J. M. (2007). Distribution and physiology of ABC-type transporters contributing to multidrug resistance in bacteria. Microbiol. Mol. Biol. Rev. 71, 463-476. doi: 10.1128/MMBR.00001-07
79. Marchetti, M. L., Errecalde, J., and Mestorino, N. (2012). Effect of 1-(1-naphthylmethyl)-piperazine on antimicrobial agent susceptibility in multidrug-resistant isogenic and veterinary Escherichia coli field strains. J. Med. Microbiol. 61, 786-792. doi: 10.1099/jmm.0.040204-0
80. Martins, A., Spengler, G., Rodrigues, L., Viveiros, M., Ramos, J., Martins, M., et al. (2009). pH Modulation of efflux pump activity of multi-drug resistant Escherichia coli: protection during its passage and eventual colonization of the colon. PLoS ONE 4:e6656. doi: 10.1371/journal.pone.0006656
81. Masi, M., and Pagès, J.-M. (2013). Structure, function and regulation of outer membrane proteins involved in drug transport in Enterobactericeae: the OmpF/C - TolC case. Open Microbiol. J. 7, 22-33. doi: 10.2174/1874285801307010022
82. Matsumura, K., Furukawa, S., Ogihara, H., and 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
83. Matsumura, Y., Yamamoto, M., Nagao, M., Ito, Y., Takakura, S., and Ichiyama, S. (2013). Association of fluoroquinolone resistance, virulence genes, and IncF plasmids with extended-spectrum-β-lactamase-producing Escherichia coli sequence type 131 (ST131) and ST405 clonal groups. Antimicrob. Agents Chemother. 57, 4736-4742. doi: 10.1128/AAC.00641-13
84. Mealman, T. D., Zhou, M., Affandi, T., Chacón, K. N., Aranguren, M. E., Blackburn, N. J., et al. (2012). N-terminal region of CusB is sufficient for metal binding and metal transfer with the metallochaperone CusF. Biochemistry 51, 6767-6775. doi: 10.1021/bi300596a
85. Merritt, M. E., and Donaldson, J. R. (2009). Effect of bile salts on the DNA and membrane integrity of enteric bacteria. J. Med. Microbiol. 58, 1533-1541. doi: 10.1099/jmm.0.014092-0
86. Michael, C. A., Dominey-Howes, D., and Labbate, M. (2014). The antimicrobial resistance crisis: causes, consequences, and management. Front. Public Health 2:145. doi: 10.3389/fpubh.2014.00145
87. Misra, R., Morrison, K. D., Cho, H. J., and Khuu, T. (2015). Importance of real-time assays to distinguish multidrug efflux pump inhibiting and outer membrane destabilizing activities in Escherichia coli. J. Bacteriol. doi: 10.1128/JB.02456-14 [Epub ahead of print].
88. Money, P., Kelly, A. F., Gould, S. W. J., Denholm-Price, J., Threlfall, E. J., and Fielder, M. D. (2010). Cattle, weather and water: mapping Escherichia coli O157:H7 infections in humans in England and Scotland. Environ. Microbiol. 12, 2633-2644. doi: 10.1111/j.1462-2920.2010.02293.x
89. Moon, D. C., Seol, S. Y., Gurung, M., Jin, J. S., Choi, C. H., Kim, J., et al. (2010). Emergence of a new mutation and its accumulation in the topoisomerase IV gene confers high levels of resistance to fluoroquinolones in Escherichia coli isolates. Int. J. Antimicrob. Agents 35, 76-79. doi: 10.1016/j.ijantimicag.2009.08.003
90. Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T., and Yamaguchi, A. (2006). Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443, 173-179. doi: 10.1038/nature05076
91. Murakami, S., Nakashima, R., Yamashita, E., and Yamaguchi, A. (2002). Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419, 587-593. doi: 10.1038/nature01050
92. Nagakubo, S., Nishino, K., Hirata, T., and 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
93. Nakashima, R., Sakurai, K., Yamasaki, S., Nishino, K., and Yamaguchi, A. (2011). Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature 480, 565-569. doi: 10.1038/nature10641
94. Nies, D. H. (2003). Efflux-mediated heavy metal resistance in prokaryotes. FEMS Microbiol. Rev. 27, 313-339. doi: 10.1016/S0168-6445(03)00048-2
95. Nikaido, H. (1996). Multidrug efflux pumps of gram-negative bacteria. J. Bacteriol. 178, 5853-5859.
96. Nikaido, H. (2011). Structure and mechanism of RND-type multidrug efflux pumps. Adv. Enzymol. Relat. Areas Mol. Biol. 77, 1-60. doi: 10.1002/9780470920541.ch1
97. Nikaido, H., and Pagès, J. -M. (2012). Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol. Rev. 36, 340-363. doi: 10.1111/j.1574-6976.2011.00290.x
98. Nikaido, H., and Takatsuka, Y. (2009). Mechanisms of RND multidrug efflux pumps. Biochim. Biophys. Acta 1794, 769-781. doi: 10.1016/j.bbapap.2008.10.004
99. Nishino, K., Senda, Y., Hayashi-Nishino, M., and 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
100. Nishino, K., Senda, Y., and Yamaguchi, A. (2008a). CRP regulator modulates multidrug resistance of Escherichia coli by repressing the mdtEF multidrug efflux genes. J. Antibiot. (Tokyo) 61, 120-127. doi: 10.1038/ja.2008.120
101. Nishino, K., Senda, Y., and Yamaguchi, A. (2008b). 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
102. Nishino, K., and 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
103. Nishino, K., and 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
104. Nishino, K., and 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
105. Nishino, K., Yamasaki, S., Hayashi-Nishino, M., and 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
106. Nishino, K., Yamasaki, S., Hayashi-Nishino, M., and 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
107. Olesen, B., Hansen, D. S., Nilsson, F., Frimodt-Møller, J., Leihof, R. F., Struve, C., et al. (2013). Prevalence and characteristics of the epidemic multiresistant Escherichia coli ST131 clonal group among extended-spectrum beta-lactamase-producing E. coli isolates in Copenhagen, Denmark. J. Clin. Microbiol. 51, 1779-1785. doi: 10.1128/JCM.00346-13
108. Opperman, T. J., Kwasny, S. M., Kim, H.-S., Nguyen, S. T., Houseweart, C., D'Souza, S., 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
109. Peltier, E., Vincent, J., Finn, C., and Graham, D. W. (2010). Zinc-induced antibiotic resistance in activated sludge bioreactors. Water Res. 44, 3829-3836. doi: 10.1016/j.watres.2010.04.041
110. Pennington, T. H. (2014). E. coli O157 outbreaks in the United Kingdom: past, present, and future. Infect. Drug Resist. 7, 211-222. doi: 10.2147/IDR.S49081
111. Perreten, V., Schwarz, F. V., Teuber, M., and Levy, S. B. (2001). Mdt(A), a new efflux protein conferring multiple antibiotic resistance in Lactococcus lactis and Escherichia coli. Antimicrob. Agents Chemother. 45, 1109-1114. doi: 10.1128/AAC.45.4.1109-1114.2001
112. Piddock, L. J. V. (2006). Multidrug-resistance efflux pumps - not just for resistance. Nat. Rev. Microbiol. 4, 629-636. doi: 10.1038/nrmicro1464
113. Poole, K. (2002). Mechanisms of bacterial biocide and antibiotic resistance. J. Appl. Microbiol. 92(Suppl. s1), 55S-64S. doi: 10.1046/j.1365-2672.92.5s1.8.x
114. Poole, K. (2007). Efflux pumps as antimicrobial resistance mechanisms. Ann. Med. 39, 162-176. doi: 10.1080/07853890701195262
115. Pos, K. M. (2009). Drug transport mechanism of the AcrB efflux pump. Biochim. Biophys. Acta 1794, 782-793. doi: 10.1016/j.bbapap.2008.12.015
116. Rademacher, C., and Masepohl, B. (2012). Copper-responsive gene regulation in bacteria. Microbiology 158, 2451-2464. doi: 10.1099/mic.0.058487-0
117. Radhakrishnan, V., Ganguly, K., Ganguly, M., Dastidar, S. G., and Chakrabarty, A. N. (1999). Potentiality of tricyclic compound thioridazine as an effective antibacterial and antiplasmid agent. Indian J. Exp. Biol. 37, 671-675.
118. Radosavljevic, V., Finke, E.-J., and Belojevic, G. (2014). Escherichia coli O104:H4 outbreak in Germany-clarification of the origin of the epidemic. Eur. J. Public Health 25, 125-129. doi: 10.1093/eurpub/cku048
119. Rahmati, S., Yang, S., Davidson, A. L., and Zechiedrich, E. L. (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
120. Rosenberg, E. Y., Bertenthal, D., Nilles, M. L., Bertrand, K. P., and 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
121. Rosenberg, E. Y., Ma, D., and 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
122. Rosner, J. L., and Martin, R. G. (2009). An excretory function for the Escherichia coli outer membrane pore TolC: upregulation of marA and soxS transcription and Rob activity due to metabolites accumulated in tolC mutants. J. Bacteriol. 191, 5283-5292. doi: 10.1128/JB.00507-09
123. Ruiz, C., and Levy, S. B. (2014). Regulation of acrAB expression by cellular metabolites in Escherichia coli. J. Antimicrob. Chemother. 69, 390-399. doi: 10.1093/jac/dkt352
124. Seeger, M. A., Schiefner, A., Eicher, T., Verrey, F., Diederichs, K., and Pos, K. M. (2006). Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313, 1295-1298. doi: 10.1126/science.1131542
125. Sennhauser, G., Amstutz, P., Briand, C., Storchenegger, O., and Grütter, M. G. (2007). Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol. 5:e7. doi: 10.1371/journal.pbio.0050007
126. Shah, A. A., Wang, C., Chung, Y.-R., Kim, J.-Y., Choi, E.-S., and Kim, S.-W. (2013). Enhancement of geraniol resistance of Escherichia coli by MarA overexpression. J. Biosci. Bioeng. 115, 253-258. doi: 10.1016/j.jbiosc.2012.10.009
127. Shimada, T., Shimada, K., Matsui, M., Kitai, Y., Igarashi, J., Suga, H., et al. (2014). Roles of cell division control factor SdiA: recognition of quorum sensing signals and modulation of transcription regulation targets. Genes Cells 19, 405-418. doi: 10.1111/gtc.12139
128. Spengler, G., Miczák, A., Hajdú, E., Kawase, M., Amaral, L., and Molnár, J. (2003). Enhancement of plasmid curing by 9-aminoacridine and two phenothiazines in the presence of proton pump inhibitor 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone. Int. J. Antimicrob. Agents 22, 223-227. doi: 10.1016/S0924-8579(03)00207-3
129. Su, C.-C., Long, F., Lei, H.-T., Bolla, J. R., Do, S. V., Rajashankar, K. R., et al. (2012). Charged amino acids (R83, E567, D617, E625, R669, and K678) of CusA are required for metal ion transport in the Cus efflux system. J. Mol. Biol. 422, 429-441. doi: 10.1016/j.jmb.2012.05.038
130. Su, C.-C., Long, F., and Yu, E. W. (2011a). The Cus efflux system removes toxic ions via a methionine shuttle. Protein Sci. 20, 6-18. doi: 10.1002/pro.532
131. Su, C.-C., Long, F., Zimmermann, M. T., Rajashankar, K. R., Jernigan, R. L., and Yu, E. W. (2011b). Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli. Nature 470, 558-562. doi: 10.1038/nature09743
132. Su, C.-C., Yang, F., Long, F., Reyon, D., Routh, M. D., Kuo, D. W., et al. (2009). Crystal structure of the membrane fusion protein CusB from Escherichia coli. J. Mol. Biol. 393, 342-355. doi: 10.1016/j.jmb.2009.08.029
133. Sulavik, M. C., Houseweart, C., Cramer, C., Jiwani, N., Murgolo, N., Greene, J., 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
134. Symmons, M. F., Bokma, E., Koronakis, E., Hughes, C., and Koronakis, V. (2009). The assembled structure of a complete tripartite bacterial multidrug efflux pump. Proc. Natl. Acad. Sci. U.S.A. 106, 7173-7178. doi: 10.1073/pnas.0900693106
135. Tal, N., and 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
136. Tanabe, M., Szakonyi, G., Brown, K. A., Henderson, P. J. F., Nield, J., and Byrne, B. (2009). The multidrug resistance efflux complex, EmrAB from Escherichia coli forms a dimer in vitro. Biochem. Biophys. Res. Commun. 380, 338-342. doi: 10.1016/j.bbrc.2009.01.081
137. Tavío, M. M., Aquili, V. D., Poveda, J. B., Antunes, N. T., Sánchez-Céspedes, J., and Vila, J. (2010). Quorum-sensing regulator sdiA and marA overexpression is involved in in vitro-selected multidrug resistance of Escherichia coli. J. Antimicrob. Chemother. 65, 1178-1186. doi: 10.1093/jac/dkq112
138. Thanassi, D. G., Cheng, L. W., and Nikaido, H. (1997). Active efflux of bile salts by Escherichia coli. J. Bacteriol. 179, 2512-2518.
139. Tikhonova, E. B., Dastidar, V., Rybenkov, V. V., and Zgurskaya, H. I. (2009). Kinetic control of TolC recruitment by multidrug efflux complexes. Proc. Natl. Acad. Sci. U.S.A. 106, 16416-16421. doi: 10.1073/pnas.090601106
140. Tikhonova, E. B., Yamada, Y., and Zgurskaya, H. I. (2011). Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. Chem. Biol. 18, 454-463. doi: 10.1016/j.chembiol.2011.02.011
141. Tikhonova, E. B., and Zgurskaya, H. I. (2004). AcrA, AcrB, and TolC of Escherichia coli form a stable intermembrane multidrug efflux complex. J. Biol. Chem. 279, 32116-32124. doi: 10.1074/jbc.M402230200
142. Touzé, T., Eswaran, J., Bokma, E., Koronakis, E., Hughes, C., and Koronakis, V. (2004). Interactions underlying assembly of the Escherichia coli AcrAB-TolC multidrug efflux system. Mol. Microbiol. 53, 697-706. doi: 10.1111/j.1365-2958.2004.04158.x
143. Turlin, E., Heuck, G., Brandão, M. I. S., Szili, N., Mellin, J. R., Lange, N., et al. (2014). Protoporphyrin (PPIX) efflux by the MacAB-TolC pump in Escherichia coli. Microbiologyopen 3, 849-859. doi: 10.1002/mbo3.203
144. Vargiu, A. V., Ruggerone, P., Opperman, T. J., Nguyen, S. T., and Nikaido, H. (2014). Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob. Agents Chemother. 58, 6224-6234. doi: 10.1128/AAC.03283-14
145. Viveiros, M., Jesus, A., Brito, M., Leandro, C., Martins, M., Ordway, D., 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
146. Viveiros, M., Martins, A., Paixão, L., Rodrigues, L., Martins, M., Couto, I., et al. (2008). Demonstration of intrinsic efflux activity of Escherichia coli K-12 AG100 by an automated ethidium bromide method. Int. J. Antimicrob. Agents 31, 458-462. doi: 10.1016/j.ijantimicag.2007.12.015
147. Wang, D., and Fierke, C. A. (2013). The BaeSR regulon is involved in defense against zinc toxicity in E. coli. Metallomics 5, 372-383. doi: 10.1039/c3mt20217h
148. Wang, H., Dzink-Fox, J. L., Chen, M., and Levy, S. B. (2001). Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations. Antimicrob. Agents Chemother. 45, 1515-1521. doi: 10.1128/AAC.45.5.1515-1521.2001
149. Warner, D. M., and Levy, S. B. (2010). Different effects of transcriptional regulators MarA, SoxS and Rob on susceptibility of Escherichia coli to cationic antimicrobial peptides (CAMPs): rob-dependent CAMP induction of the marRAB operon. Microbiology 156, 570-578. doi: 10.1099/mic.0.033415-0
150. Weeks, J. W., Celaya-Kolb, T., Pecora, S., and Misra, R. (2010). AcrA suppressor alterations reverse the drug hypersensitivity phenotype of a TolC mutant by inducing TolC aperture opening. Mol. Microbiol. 75, 1468-1483. doi: 10.1111/j.1365-2958.2010.07068.x
151. Wei, Y., Lee, J. M., Smulski, D. R., and LaRossa, R. A. (2001). Global impact of sdiA amplification revealed by comprehensive gene expression profiling of Escherichia coli. J. Bacteriol. 183, 2265-2272. doi: 10.1128/JB.183.7.2265-2272.2001
152. World Health Organization (WHO). (2014). Antimicrobial Resistance: Global Report on Surveillance 2014. Geneva: WHO.
153. Xu, Y., Lee, M., Moeller, A., Song, S., Yoon, B.-Y., Kim, H.-M., et al. (2011). Funnel-like hexameric assembly of the periplasmic adapter protein in the tripartite multidrug efflux pump in gram-negative bacteria. J. Biol. Chem. 286, 17910-17920. doi: 10.1074/jbc.M111.238535
154. Xu, Y., Moeller, A., Jun, S.-Y., Le, M., Yoon, B.-Y., Kim, J.-S., et al. (2012). Assembly and channel opening of outer membrane protein in tripartite drug efflux pumps of Gram-negative bacteria. J. Biol. Chem. 287, 11740-11750. doi: 10.1074/jbc.M111.329375
155. Xue, Y., Davis, A. V., Balakrishnan, G., Stasser, J. P., Staehlin, B. M., Focia, P., et al. (2008). Cu(I) recognition via cation-pi and methionine interactions in CusF. Nat. Chem. Biol. 4, 107-109. doi: 10.1038/nchembio.2007.57
156. Yang, D., Weatherspoon-Griffin, N., Kong, W., Hua, Z., and Shi, Y. (2014). The CpxR/CpxA two-component regulatory system upregulates the multidrug resistance cascade to facilitate Escherichia coli resistance to a model antimicrobial peptide. J. Biol. Chem. 289, 32571-32582. doi: 10.1074/jbc.M114.565762
157. Yu, E. W., McDermott, G., Zgurskaya, H. I., Nikaido, H., and Koshland, D. E. (2003). Structural basis of multiple drug-binding capacity of the AcrB multidrug efflux pump. Science 300, 976-980. doi: 10.1126/science.1083137
158. Yum, S., Xu, Y., Piao, S., Sim, S.-H., Kim, H.-M., Jo, W.-S., et al. (2009). Crystal structure of the periplasmic component of a tripartite macrolide-specific efflux pump. J. Mol. Biol. 387, 1286-1297. doi: 10.1016/j.jmb.2009.02.048
159. Zgurskaya, H. I., and Nikaido, H. (2000). Cross-linked complex between oligomeric periplasmic lipoprotein AcrA and the inner-membrane-associated multidrug efflux pump AcrB from Escherichia coli. J. Bacteriol. 182, 4264-4267. doi: 10.1128/JB.182.15.4264-4267.2000
160. Zhang, Y., Xiao, M., Horiyama, T., Zhang, Y., Li, X., Nishino, K., et al. (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