Advertisement

Efflux pump-mediated antibiotics resistance: Insights from computational structural biology

  • Nadine Fischer
  • Martin Raunest
  • Thomas H. Schmidt
  • Dennis C. Koch
  • Christian KandtEmail author
Article

Abstract

The continuous rise of bacterial resistance against formerly effective pharmaceuticals is a major challenge for biomedical research. Since the first computational studies published seven years ago the simulation-based investigation of antibiotics resistance mediated by multidrug efflux pumps of the resistance nodulation division (RND) protein super family has grown into a vivid field of research. Here we review the employment of molecular dynamics computer simulations to investigate RND efflux pumps focusing on our group’s recent contributions to this field studying questions of energy conversion and substrate transport in the inner membrane antiporter AcrB in Escherichia coli as well as access regulation and gating mechanism in the outer membrane efflux ducts TolC and OprM in E. coli and Pseudomonas aeruginosa.

Key words

molecular dynamics simulation AcrB TolC OprM proton conduction multidrug transport access regulation membrane protein 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    Abresch, E.C., Paddock, M.L., Stowell, M.H.B., McPhillips, T.M., Axelrod, H.L., Soltis, S.M., Rees, D.C., Okamura, M.Y., Feher, G. 1998. Identification of proton transfer pathways in the X-ray crystal structure of the bacterial reaction center from Rhodobacter sphaeroides. Photosynth Res 55, 119–125.Google Scholar
  2. [2]
    Akama, H., Kanemaki, M., Yoshimura, M., Tsukihara, T., Kashiwagi, T., Yoneyama, H., Narita, S., Nakagawa, A., Nakae, T. 2004. Crystal structure of the drug discharge outer membrane protein, OprM, of Pseudomonas aeruginosa: Dual modes of membrane anchoring and occluded cavity end. J Biol Chem 279, 52816–52819.PubMedGoogle Scholar
  3. [3]
    Andersen, C., Koronakis, E., Bokma, E., Eswaran, J., Humphreys, D., Hughes, C., Koronakis, V. 2002a. Transition to the open state of the TolC periplasmic tunnel entrance. Proc Natl Acad Sci USA 99, 11103–11108.PubMedGoogle Scholar
  4. [4]
    Andersen, C., Koronakis, E., Hughes, C., Koronakis, V. 2002b. An aspartate ring at the TolC tunnel entrance determines ion selectivity and presents a target for blocking by large cations. Mol Microbiol 44, 1131–1139.PubMedGoogle Scholar
  5. [5]
    Aqvist, J., Warshel, A. 1993. Simulation of enzymereactions using valence-bond force-fields and other hybrid quantum-classical approaches. Chem Rev 93, 2523–2544.Google Scholar
  6. [6]
    Arkin, I.T., Xu, H., Jensen, M.O., Arbely, E., Bennett, E.R., Bowers, K.J., Chow, E., Dror, R.O., Eastwood, M.P., Flitman-Tene, R., Gregersen, B.A., Klepeis, J.L., Kolossvary, I., Shan, Y., Shaw, D.E. 2007. Mechanism of Na+/H+ antiporting. Science 317, 799–803.PubMedGoogle Scholar
  7. [7]
    Bajorath, J. 2010. Chemoinformatics and Computational Chemical Biology. Methods in Molecular Biology. Humana Press, New York.Google Scholar
  8. [8]
    Bandow, J.E., Metzler-Nolte, N. 2009. New ways of killing the beast: Prospects for inorganic-organic hybrid nanomaterials as antibacterial agents. Chembiochem 10, 2847–2850.PubMedGoogle Scholar
  9. [9]
    Bavro, V.N., Pietras, Z., Furnham, N., Pérez-Cano, L., FernÃindez-Recio, J., Pei, X.Y., Misra, R., Luisi, B. 2008. Assembly and channel opening in a bacterial drug efflux machine. Mol Cell 30, 114–121.PubMedCentralPubMedGoogle Scholar
  10. [10]
    Baxevanis, A.D., Ouellette, B.F.F. 2005. Bioinformatics — A Practical Guide to the Analysis of Genes and Proteins. John Wiley & Sons, Hoboken.Google Scholar
  11. [11]
    Bourne, P.E., Weissig, H. 2003. Structural Bioinformatics. Methods of Biochemical Analysis. John Wiley & Sons, Hoboken.Google Scholar
  12. [12]
    Cohen, R. 2006. Approaches to reduce antibiotic resistance in the community. Pediat Inf Dis J 25, 977–980.Google Scholar
  13. [13]
    Collu, F., Vargiu, A.V., Dreier, J., Cascella, M., Ruggerone, P. 2012. Recognition of Imipenem and Meropenem by RND-transporter MexB studied by computer simulations. J Am Chem Soc 134, 19146–19158.PubMedGoogle Scholar
  14. [14]
    Dougherty, T.J., Barrett, J.F., Pucci, M.J. 2002. Microbial genomics and novel antibiotic discovery: New technology to search for new drugs. Curr Pharm Design 8, 1119–1135.Google Scholar
  15. [15]
    Eicher, T., Cha, H.J., Seeger, M.A., Brandstatter, L., El-Delik, J., Bohnert, J.A., Kern, W.V., Verrey, F., Grutter, M.G., Diederichs, K., Pos, K.M. 2012. Transport of drugs by the multidrug transporter AcrB involves an access and a deep binding pocket that are separated by a switch-loop. Proc Natl Acad Sci USA 109, 5687–5692.PubMedGoogle Scholar
  16. [16]
    Federici, L., Du, D., Walas, F., Matsumura, H., Fernandez-Recio, J., McKeegan, K.S., Borges-Walmsley, M.I., Luisi, B.F., Walmsley, A.R. 2005. The crystal structure of the outer membrane protein VceC from the bacterial pathogen Vibrio cholerae at 1.8 A resolution. J Biol Chem 280, 15307–15314.PubMedGoogle Scholar
  17. [17]
    Feng, Z., Hou, T., Li, Y. 2012. Unidirectional peristaltic movement in multisite drug binding pockets of AcrB from molecular dynamics simulations. Mol Biosyst 8, 2699–2709.PubMedGoogle Scholar
  18. [18]
    Fischer, N., Kandt, C. 2011. Three ways in, one way out: Water dynamics in the trans-membrane domains of the inner membrane translocase AcrB. Proteins 79, 2871–2885.PubMedGoogle Scholar
  19. [19]
    Fischer, N., Kandt, C. 2013. Porter domain opening and closing motions in the multi-drug efflux transporter AcrB. BBA — Biomembranes 1828, 632–641.PubMedGoogle Scholar
  20. [20]
    Frenkel, D., Smit, B. 2002. Understanding Molecular Simulation: From Algorithms to Applications. Academic Press, Waltham.Google Scholar
  21. [21]
    Garczarek, F., Gerwert, K. 2006. Functional waters in intraprotein proton transfer monitored by FTIR difference spectroscopy. Nature 439, 109–112.PubMedGoogle Scholar
  22. [22]
    Gotoh, N., Tsujimoto, H., Nomura, A., Okamoto, K., Tsuda, M., Nishino, T. 1998. Functional replacement of OprJ by OprM in the MexCD-OprJ multidrug efflux system of Pseudomonas aeruginosa. FEMS Microbiol Lett 165, 21–27.PubMedGoogle Scholar
  23. [23]
    Grossfield, A., Zuckerman, D.M. 2009. Quantifying uncertainty and sampling quality in biomolecular simulations. Annu Rep Comput Chem 5, 23–48.PubMedCentralPubMedGoogle Scholar
  24. [24]
    Grudinin, S., Buldt, G., Gordeliy. V., Baumgaertner, A. 2005. Water molecules and hydrogen-bonded networks in bacteriorhodopsin — molecular dynamics simulations of the ground state and the M-intermediate. Biophys J 88, 3252–3261.PubMedCentralPubMedGoogle Scholar
  25. [25]
    Guan, L., Nakae, T. 2001. Identification of essential charged residues in transmembrane segments of the multidrug transporter MexB of Pseudomonas aeruginosa. J Bacteriol 183, 1734–1739.PubMedCentralPubMedGoogle Scholar
  26. [26]
    Higgins, M.K., Eswaran, J., Edwards, P., Schertler, G.F., Hughes, C., Koronakis, V. 2004. Structure of the ligand-blocked periplasmic entrance of the bacterial multidrug efflux protein TolC. J Mol Biol 342, 697–702.PubMedGoogle Scholar
  27. [27]
    Kamerlin, S.C.L., Warshel, A. 2010. The EVB as a quantitative tool for formulating simulations and analyzing biological and chemical reactions. Faraday Discuss 145, 71–106.Google Scholar
  28. [28]
    Kandt, C., Gerwert, K., Schlitter, J. 2005. Water dynamics simulation as a tool for probing proton transfer pathways in a heptahelical membrane protein. Proteins 58, 528–537.PubMedGoogle Scholar
  29. [29]
    Kandt, C., Monticelli, L. 2010. Membrane protein dynamics from femtoseconds to seconds. Methods Mol Biol 654, 423–440.PubMedGoogle Scholar
  30. [30]
    Kandt, C., Schlitter, J., Gerwert, K. 2004. Dynamics of water molecules in the bacteriorhodopsin trimer in explicit lipid/water environment. Biophys J 86, 705–717.PubMedCentralPubMedGoogle Scholar
  31. [31]
    Koch, D.C., Raunest, M., Harder, T., Kandt, C. 2013. Unilateral access regulation: Ground state dynamics of the Pseudomonas aeruginosa outer membrane efflux duct OprM. Biochemistry 52, 178–187.PubMedGoogle Scholar
  32. [32]
    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.PubMedGoogle Scholar
  33. [33]
    Kukol, A. 2008. Molecular Modeling of Proteins. Methods in Molecular Biology. Humana Press, Totowa.Google Scholar
  34. [34]
    Kulathila, R., Indic, M., 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.PubMedCentralPubMedGoogle Scholar
  35. [35]
    Lanyi, J.K. 2004. Bacteriorhodopsin. Annu Rev Physiol 66, 665–688.PubMedGoogle Scholar
  36. [36]
    Larijani, B., Rosser, C.A., Woscholski, R. 2006. Chemical Biology — Techniques and Applications. JohnWiley & Sons Ltd., Chichester.Google Scholar
  37. [37]
    Leach, A.R. 2001. Molecular Modelling — Principles and Applications. Pearson Education Limited, Essex.Google Scholar
  38. [38]
    Lill, M.A., Helms, V. 2001. Molecular dynamics simulation of proton transport with quantum mechanically derived proton hopping rates (Q-HOP MD). J Chem Phys 115, 7993–8005.Google Scholar
  39. [39]
    Lobedanz, S., Bokma, E., Symmons, M.F., Koronakis, E., Hughes, C., Koronakis, V. 2007. A periplasmic coiled-coil interface underlying TolC recruitment and the assembly of bacterial drug efflux pumps. Proc Natl Acad Sci USA 104, 4612–4617.PubMedGoogle Scholar
  40. [40]
    Lottspeich, F., Engels, J.W. 2006. Bioanalytik. Elsevier, Heildelberg.Google Scholar
  41. [41]
    Lu, W.C., Wang, C.Z., Yu, E.W., Ho, K.M. 2006. Dynamics of the trimeric AcrB transporter protein inferred from a B-factor analysis of the crystal structure. Proteins 62, 152–158.PubMedCentralPubMedGoogle Scholar
  42. [42]
    Luecke, H. 2000. Atomic resolution structures of bacteriorhodopsin photocycle intermediates: the role of discrete water molecules in the function of this lightdriven ion pump. BBA — Bioenergetics 1460, 133–156.PubMedGoogle Scholar
  43. [43]
    Ma, D., Cook, D.N., Alberti, M., Pon, N.G., Nikaido, H., Hearst, J.E. 1993. Molecular cloning and characterization of acrA and acrE genes of Escherichia coli. J Bacteriol 175, 6299–6313.PubMedCentralPubMedGoogle Scholar
  44. [44]
    Marrink, S., Devries, A., Tieleman, D. 2009. Lipids on the move: Simulations of membrane pores, domains, stalks and curves. BBA — Biomembranes 1788, 149–168.PubMedGoogle Scholar
  45. [45]
    Marx, D. 2006. Proton transfer 200 years after von Grotthuss: Insights from ab initio simulations. Chemphyschem 7, 1848–1870.PubMedGoogle Scholar
  46. [46]
    McDevitt, D., Rosenberg, M. 2001. Exploiting genomics to discover new antibiotics. Trends Microbiol 9, 611–617.PubMedGoogle Scholar
  47. [47]
    Mikolosko, J., Bobyk, K., Zgurskaya, H.I., Ghosh, P. 2006. Conformational flexibility in the multidrug efflux system protein AcrA. Structure 14, 577–587.PubMedCentralPubMedGoogle Scholar
  48. [48]
    Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T., Yamaguchi, A. 2002. Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419, 587–593.PubMedGoogle Scholar
  49. [49]
    Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T., Yamaguchi, A. 2006. Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443, 173–179.PubMedGoogle Scholar
  50. [50]
    Murakami, S., Yamaguchi, A. 2003. Multidrugexporting secondary transporters. Curr Opin Struct Biol 13, 443–452.PubMedGoogle Scholar
  51. [51]
    Nakashima, R., Sakurai, K., Yamasaki, S., Nishino, K., Yamaguchi, A. 2011. Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature 480, 565–569.PubMedGoogle Scholar
  52. [52]
    Nikaido, H. 1996. Multidrug efflux pumps of gramnegative bacteria. J Bacteriol 178, 5853–5859.PubMedCentralPubMedGoogle Scholar
  53. [53]
    Nikaido, H. 1998. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis 27, S32–S41.PubMedGoogle Scholar
  54. [54]
    Nikaido, H. 2009. Multidrug resistance in bacteria. Annu Rev Biochem 27, 32–41.Google Scholar
  55. [55]
    Nikaido, H. 2011. Structure and mechanism of RNDtype multidrug efflux pumps. Adv Enzymol Relat Areas Mol Biol 77, 1–60.PubMedCentralPubMedGoogle Scholar
  56. [56]
    Nussinov, R., Schreiber, G. 2009. Computational Protein. CRC Press, Taylor & Francis Group, Boca Raton, London, New York.Google Scholar
  57. [57]
    Pei, X.Y., Hinchliffe, P., Symmons, M.F., Koronakis, E., Benz, R., Hughes, C., Koronakis, V. 2010. Structures of sequential open states in a symmetrical opening transition of the TolC exit duct. Proc Natl Acad Sci USA 108, 2112–2117.Google Scholar
  58. [58]
    Phan, G., Benabdelhak, H., Lascombe, M.B., Benas, P., Rety, S., Picard, M., Ducruix, A., Etchebest, C., Broutin, I. 2010. Structural and dynamical insights into the opening mechanism of P. aeruginosa OprM channel. Structure 18, 507–517.Google Scholar
  59. [59]
    Piddock, L.J.V. 2006. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19, 382–402.PubMedCentralPubMedGoogle Scholar
  60. [60]
    Pisliakov, A.V., Hino, T., Shiro, Y., Sugita, Y. 2012. Molecular dynamics simulations reveal proton transfer pathways in cytochrome C-dependent nitric oxide reductase. PLoS Comput Biol 8, e1002674.PubMedCentralPubMedGoogle Scholar
  61. [61]
    Raunest, M., Kandt, C. 2012. Locked on one side only: Ground state dynamics of the outer membrane efflux duct TolC. Biochemistry 51, 1719–1729.PubMedGoogle Scholar
  62. [62]
    Rhodes, G. 2006. Crystallography Made Crystal Clear. Elsevier, London.Google Scholar
  63. [63]
    Ruggerone, P., Vargiu, A.V., Fischer, N., Kandt, C. 2013. Molecular dynamics computer wimulation of RND effllux pumps. CSBJ 5, e2013302008.Google Scholar
  64. [64]
    Saier, M.H. Jr., Paulsen, I.T. 2001. Phylogeny of multidrug transporters. Semin Cell Dev Biol 12, 205–213.PubMedGoogle Scholar
  65. [65]
    Schlick, T. 2002. Molecular Modeling and Simulation: An Interdisciplinary Guide. Springer, New York.Google Scholar
  66. [66]
    Schmidt, T.H., O’Mara, M.L., Kandt, C. 2012. Molecular dynamics simulations of membrane proteins: Building starting structures and example applications. Curr Phys Chem 2, 363–378.Google Scholar
  67. [67]
    Schmitt, U.W., Voth, G.A. 1998. Multistate empirical valence bond model for proton transport in water. J Phys Chem B 102, 5547–5551.Google Scholar
  68. [68]
    Schulz, R., Kleinekathöfer, U. 2009. Transitions between closed and open conformations of TolC: The effects of ions in simulations. Biophys J 96, 3116–3125.PubMedCentralPubMedGoogle Scholar
  69. [69]
    Schulz, R., Vargiu, A.V., Collu, F., Kleinekathofer, U., Ruggerone, P. 2010. Functional rotation of the transporter AcrB: Insights into drug extrusion from simulations. PLoS Comput Biol 6, e1000806.PubMedCentralPubMedGoogle Scholar
  70. [70]
    Schulz, R., Vargiu, A.V., Ruggerone, P., Kleinekathofer, U. 2011. Role of water during the extrusion of substrates by the efflux transporter AcrB. J Phys Chem B 115, 8278–8287.PubMedGoogle Scholar
  71. [71]
    Seeger, M.A., Schiefner, A., Eicher, T., Verrey, F., Diederichs, K., Pos, K.M. 2006. Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313, 1295–1298.PubMedGoogle Scholar
  72. [72]
    Seeger, M.A., von Ballmoos, C., Verrey, F., Pos, K.M. 2009. Crucial role of Asp408 in the proton translocation pathway of multidrug transporter AcrB: Evidence from site-directed mutagenesis and carbodiimide labeling. Biochemistry 48, 5801–5812.PubMedGoogle Scholar
  73. [73]
    Sennhauser, G., Amstutz, P., Briand, C., Storchenegger, O., Grutter, M.G. 2007. Drug export pathway of multidrug exporter AcrB revealed by DARPin inhibitors. PLoS Biol 5, e7.PubMedCentralPubMedGoogle Scholar
  74. [74]
    Sennhauser, G., Bukowska, M.A., Briand, C., Grutter, M.G. 2009. Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. J Mol Biol 389, 134–145.PubMedGoogle Scholar
  75. [75]
    Shaw, D.E., Maragakis, P., Lindorff-Larsen, K., Piana, S., Dror, R.O., Eastwood, M.P., Bank, J.A., Jumper, J.M., Salmon, J.K., Shan, Y.B., Wriggers, W. 2010. Atomic-level characterization of the structural dynamics of proteins. Science 330, 341–346.PubMedGoogle Scholar
  76. [76]
    Sherwood, P., Brooks, B.R., Sansom, M.S.P. 2008. Multiscale methods for macromolecular simulations. Curr Opin Struct Biol 18, 630–640.PubMedGoogle Scholar
  77. [77]
    Su, C.C., Li, M., Gu, R., Takatsuka, Y., McDermott, G., Nikaido, H., Yu, E.W. 2006. Conformation of the AcrB multidrug efflux pump in mutants of the putative proton relay pathway. J Bacteriol 188, 7290–7296.PubMedCentralPubMedGoogle Scholar
  78. [78]
    Su, C.C., Long, F., Zimmermann, M.T., Rajashankar, K.R., Jernigan, R.L., Yu, E.W. 2011. Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli. Nature 470, 558–562.PubMedCentralPubMedGoogle Scholar
  79. [79]
    Su, C.C., Yang, F., Long, F., Reyon, D., Routh, M.D., Kuo, D.W., Mokhtari, A.K., Van Ornam, J.D., Rabe, K.L., Hoy, J.A., Lee, Y.J., Rajashankar, K.R., Yu, E.W. 2009. Crystal structure of the membrane fusion protein CusB from Escherichia coli. J Mol Biol 393, 342–355.PubMedCentralPubMedGoogle Scholar
  80. [80]
    Svensson-Ek, M., Abramson, J., Larsson, G., Tornroth, S., Brzezinski, P., Iwata, S. 2002. The X-ray crystal structures of wild-type and EQ(I-286) mutant cytochrome c oxidases from Rhodobacter sphaeroides. J Mol Biol 321, 329–339.PubMedGoogle Scholar
  81. [81]
    Symmons, M.F., Bokma, E., Koronakis, E., Hughes, C., Koronakis, V. 2009. The assembled structure of a complete tripartite bacterial multidrug efflux pump. Proc Natl Acad Sci USA 106, 7173–7178.PubMedGoogle Scholar
  82. [82]
    Takatsuka, Y., Nikaido, H. 2006. Threonine-978 in the transmembrane segment of the multidrug efflux pump AcrB of Escherichia coli is crucial for drug transport as a probable component of the proton relay network. J Bacteriol 188, 7284–7289.PubMedCentralPubMedGoogle Scholar
  83. [83]
    Taylor, W.R., Aszódi, A. 2005. Protein Geometry, Classification, Topology and Symmetry — A Computational Analysis of Structure. IOP Publishing, London.Google Scholar
  84. [84]
    Tikhonova, E.B., Yamada, Y., Zgurskaya, H.I. 2011. Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. Chem Biol 18, 454–463.PubMedCentralPubMedGoogle Scholar
  85. [85]
    Tuckerman, M.E., Marx, D., Klein, M.L., Parrinello, M. 1997. On the quantum nature of the shared proton in hydrogen bonds. Science 275, 817–820.PubMedGoogle Scholar
  86. [86]
    Vaccaro, L., Koronakis, V., Sansom, M.S. 2006. Flexibility in a drug transport accessory protein: Molecular dynamics simulations of MexA. Biophys J 91, 558–564.PubMedCentralPubMedGoogle Scholar
  87. [87]
    Vaccaro, L., Scott, K.A., Sansom, M.S.P. 2008. Gating at both ends and breathing in the middle: Conformational dynamics of TolC. Biophys J 95, 5681–5691.PubMedCentralPubMedGoogle Scholar
  88. [88]
    Vargiu, A.V., Collu, F., Schulz, R., Pos, K.M., Zacharias, M., Kleinekathofer, U., Ruggerone, P. 2011. Effect of the F610A mutation on substrate extrusion in the AcrB transporter: Explanation and rationale by molecular dynamics simulations. J Am Chem Soc 133, 10704–10707.PubMedGoogle Scholar
  89. [89]
    Veesler, D., Blangy, S., Cambillau, C., Sciara, G. 2008. There is a baby in the bath water: AcrB contamination is a major problem in membrane-protein crystallization. Acta Crystallogr Sect F Struct Biol Cryst Commun 64, 880–885.PubMedCentralPubMedGoogle Scholar
  90. [90]
    Voth, G.A. 2009. Coarse-graining of Condensed Phase and Biomolecular Systems. CRC Press, Taylor & Francis Group, Boca Raton.Google Scholar
  91. [91]
    Wang, B., Weng, J., Fan, K., Wang, W. 2012. Interdomain flexibility and pH-induced conformational changes of AcrA revealed by molecular dynamics simulations. J Phys Chem B 116, 3411–3420.PubMedGoogle Scholar
  92. [92]
    Warshel, A. 2003. Computer simulations of enzyme catalysis: Methods, progress, and insights. Annu Rev Biophys Biomol Struct 32, 425–443.PubMedGoogle Scholar
  93. [93]
    Wax, R.G., Lewis, K., Salyers, A.A., Taber, H. 2008. Bacterial Resitance to Antimicrobials. CRC Press, Taylor & Francis Group, LLC, Boca Raton.Google Scholar
  94. [94]
    Wenzel, M., Kohl, B., Munch, D., Raatschen, N., Albada, H.B., Hamoen, L., Metzler-Nolte, N., Sahl, H.G., Bandow, J.E. 2012. Proteomic response of Bacillus subtilis to lantibiotics reflects differences in interaction with the cytoplasmic membrane. Antimicrob Agents Chemother 56, 5749–5757.PubMedCentralPubMedGoogle Scholar
  95. [95]
    World Health Organization. 2012. WHO Antimicrobial Resistance, Fact sheet °194. http://www.who.int/mediacentre/factsheets/fs194/en/.Google Scholar
  96. [96]
    Xu, Y., Lee, M., Moeller, A., Song, S., Yoon, B.Y., Kim, H.M., Jun, S.Y., Lee, K., Ha, N.C. 2011. Funnellike hexameric assembly of the periplasmic adapter protein in the tripartite multidrug efflux pump in gram-negative bacteria. J Biol Chem 286, 17910–17920.PubMedGoogle Scholar
  97. [97]
    Xu, Y., Moeller, A., Jun, S.Y., Le, M., Yoon, B.Y., Kim, J.S., Lee, K., Ha, N.C. 2012. Assembly and channel opening of outer membrane protein in tripartite drug efflux pumps of Gram-negative bacteria. J Biol Chem 287 11740–11750.PubMedGoogle Scholar
  98. [98]
    Yao, X.Q., Kenzaki, H., Murakami, S., Takada, S. 2010. Drug export and allosteric coupling in a multidrug transporter revealed by molecular simulations. Nat Commun 1, 117.PubMedCentralPubMedGoogle Scholar
  99. [99]
    Zgurskaya, H.I., Nikaido, H. 1999a. AcrA is a highly asymmetric protein capable of spanning the periplasm. J Mol Biol 285, 409–420.PubMedGoogle Scholar
  100. [100]
    Zgurskaya, H.I., Nikaido, H. 1999b. Bypassing the periplasm: Reconstitution of the AcrAB multidrug efflux pump of Escherichia coli. Proc Natl Acad Sci USA 96, 7190–7195.PubMedGoogle Scholar
  101. [101]
    Zhao, Q., Li, X.Z., Srikumar, R., Poole, K. 1998. Contribution of outer membrane efflux protein OprM to antibiotic resistance in Pseudomonas aeruginosa independent of MexAB. Antimicrob Agents Chemother 42, 1682–1688.PubMedCentralPubMedGoogle Scholar

Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Nadine Fischer
    • 1
  • Martin Raunest
    • 1
  • Thomas H. Schmidt
    • 1
  • Dennis C. Koch
    • 1
  • Christian Kandt
    • 1
    Email author
  1. 1.Computational Structural Biology, Department of Life Science Informatics B-IT, Life & Medical Sciences InstituteUniversity of BonnBonnGermany

Personalised recommendations