Multidrug Efflux Pumps and Their Inhibitors Characterized by Computational Modeling

  • Venkata Krishnan Ramaswamy
  • Pierpaolo Cacciotto
  • Giuliano Malloci
  • Paolo Ruggerone
  • Attilio V. Vargiu
Chapter

Abstract

Antimicrobial resistance is a key public health concern of our era due to an ever-increasing number of drug-resistant pathogens, including several Gram-negative bacilli. The latter are endowed with a low permeable outer membrane and with numerous chromosomally encoded multidrug efflux pumps, which are not only ubiquitous but also polyspecific, thus recognizing a broad range of compounds. Efflux pumps are a major defense mechanism of these organisms against antimicrobials as they can significantly increase the levels of resistance by allowing time for the organisms to develop specific resistance mechanisms. One of the potential strategies to reinvigorate the efficacy of antimicrobials is by joint administration with efflux pump inhibitors, which either block the substrate binding and/or hinder any of the transport-dependent steps of the pumps. In this chapter, we provide an overview of multidrug resistance efflux pumps, their inhibition strategies, and the important findings from the various computational simulation studies reported to date with respect to the rational design of inhibitors and on deciphering their mechanism of action.

Keywords

Antimicrobial resistance Efflux pump ABC MATE RND P-glycoprotein Efflux pump inhibitor Molecular dynamics Molecular docking 

References

  1. 1.
    Fauci AS (2001) Infectious diseases: considerations for the 21st century. Clin Infect Dis 32:675–685. doi:10.1086/319235 PubMedCrossRefGoogle Scholar
  2. 2.
    World Health Organization (2014) Antimicrobial resistance: global report on surveillance. World Health Organization, GenevaGoogle Scholar
  3. 3.
    Howell L (2013) Global risks 2013: an initiative of the risk response network, 8th edn. World Economic Forum, GenevaGoogle Scholar
  4. 4.
    Butler MS, Cooper MA (2011) Antibiotics in the clinical pipeline in 2011. J Antibiot (Tokyo) 64:413–425. doi:10.1038/ja.2011.44 CrossRefGoogle Scholar
  5. 5.
    Nikaido H (1994) Prevention of drug access to bacterial targets: permeability barriers and active efflux. Science 264:382–388. doi:10.1126/science.8153625 PubMedCrossRefGoogle Scholar
  6. 6.
    Poole K (2005) Efflux-mediated antimicrobial resistance. J Antimicrob Chemother 56:20–51. doi:10.1093/jac/dki171 PubMedCrossRefGoogle Scholar
  7. 7.
    Piddock LJ (2006) Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev 19:382–402. doi:10.1128/CMR.19.2.382-402.2006 PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Nikaido H, Pagès JM (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 PubMedCrossRefGoogle Scholar
  9. 9.
    Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ (2015) Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol 13:42–51. doi:10.1038/nrmicro3380 PubMedCrossRefGoogle Scholar
  10. 10.
    Lomovskaya O, Bostian KA (2006) Practical applications and feasibility of efflux pump inhibitors in the clinic – a vision for applied use. Biochem Pharmacol 71:910–918. doi:10.1016/j.bcp.2005.12.008 PubMedCrossRefGoogle Scholar
  11. 11.
    Blair JM, Richmond GE, Piddock LJ (2014) Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol 9:1165–1177. doi:10.2217/fmb.14.66 PubMedCrossRefGoogle Scholar
  12. 12.
    Li X-Z, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. doi:10.2165/11317030-000000000-00000 PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Zhang H, Wang Y-J, Zhang Y-K, Wang D-S, Kathawala RJ, Patel A, Talele TT, Chen Z-S et al (2014) AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. Cancer Lett 350:61–68. doi:10.1016/j.canlet.2014.04.008 PubMedCrossRefGoogle Scholar
  14. 14.
    Martinez L, Arnaud O, Henin E, Tao H, Chaptal V, Doshi R, Andrieu T, Dussurgey S et al (2014) Understanding polyspecificity within the substrate‐binding cavity of the human multidrug resistance P‐glycoprotein. FEBS J 281:673–682. doi:10.1111/febs.12613 PubMedCrossRefGoogle Scholar
  15. 15.
    Kim J-Y, Henrichs S, Bailly A, Vincenzetti V, Sovero V, Mancuso S, Pollmann S, Kim D et al (2010) Identification of an ABCB/P-glycoprotein-specific inhibitor of auxin transport by chemical genomics. J Biol Chem 285:23309–23317. doi:10.1074/jbc.M110.105981 PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Michaelis M, Rothweiler F, Nerreter T, Van Rikxoort M, Sharifi M, Wiese M, Ghafourian T, Cinatl J (2014) Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function. J Pharm Pharm Sci 17:154–168PubMedCrossRefGoogle Scholar
  17. 17.
    Singh DV, Godbole MM, Misra K (2013) A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors. J Mol Model 19:227–238. doi:10.1007/s00894-012-1535-8 PubMedCrossRefGoogle Scholar
  18. 18.
    Liu D-L, Li Y-J, Yao N, Xu J, Chen Z-S, Yiu A, Zhang C-X, Ye W-C et al (2014) Acerinol, a cyclolanstane triterpenoid from Cimicifuga acerina, reverses ABCB1-mediated multidrug resistance in HepG2/ADM and MCF-7/ADR cells. Eur J Pharmacol 733:34–44. doi:10.1016/j.ejphar.2014.03.043 PubMedCrossRefGoogle Scholar
  19. 19.
    Klepsch F, Vasanthanathan P, Ecker GF (2014) Ligand and structure-based classification models for prediction of P-glycoprotein inhibitors. J Chem Inf Model 54:218–229. doi:10.1021/ci400289j PubMedCrossRefGoogle Scholar
  20. 20.
    Zha W, Wang G, Xu W, Liu X, Wang Y, Zha BS, Shi J, Zhao Q et al (2013) Inhibition of P-glycoprotein by HIV protease inhibitors increases intracellular accumulation of berberine in murine and human macrophages. PLoS One 8:e54349. doi:10.1371/journal.pone.0054349 PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Zhao X-Q, Xie J-D, X-g C, Sim HM, Zhang X, Liang Y-J, Singh S, Talele TT et al (2012) Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo. Mol Pharmacol 82:47–58. doi:10.1124/mol.111.076299
  22. 22.
    Hamm R, Sugimoto Y, Steinmetz H, Efferth T (2014) Resistance mechanisms of cancer cells to the novel vacuolar H+-ATPase inhibitor archazolid B. Invest New Drugs 32:893–903. doi:10.1007/s10637-014-0134-1
  23. 23.
    Matsson P, Pedersen JM, Norinder U, Bergström CA, Artursson P (2009) Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm Res 26:1816–1831. doi:10.1007/s11095-009-9896-0 PubMedCrossRefGoogle Scholar
  24. 24.
    Abdelfatah SA, Efferth T (2015) Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells. Phytomedicine 22:308–318. doi:10.1016/j.phymed.2015.01.002 PubMedCrossRefGoogle Scholar
  25. 25.
    Munagala S, Sirasani G, Kokkonda P, Phadke M, Krynetskaia N, Lu P, Sharom FJ, Chaudhury S et al (2014) Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication. Bioorg Med Chem 22:1148–1155. doi:10.1016/j.bmc.2013.12.022 PubMedCrossRefGoogle Scholar
  26. 26.
    Brewer FK, Follit CA, Vogel PD, Wise JG (2014) In silico screening for inhibitors of P-glycoprotein that target the nucleotide binding domains. Mol Pharmacol 86:716–726. doi:10.1124/mol.114.095414 PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kim N, Shin J-M, No KT (2014) In silico study on the interaction between P-glycoprotein and its inhibitors at the drug binding pocket. Bull Korean Chem Soc 35:2317–2325. doi:10.5012/bkcs.2014.35.8.2317 CrossRefGoogle Scholar
  28. 28.
    Upadhyay HC, Dwivedi GR, Roy S, Sharma A, Darokar MP, Srivastava SK (2014) Phytol derivatives as drug resistance reversal agents. ChemMedChem 9:1860–1868. doi:10.1002/cmdc.201402027 PubMedGoogle Scholar
  29. 29.
    Zeino M, Saeed ME, Kadioglu O, Efferth T (2014) The ability of molecular docking to unravel the controversy and challenges related to P-glycoprotein – a well-known, yet poorly understood drug transporter. Invest New Drugs 32:618–625. doi:10.1007/s10637-014-0098-1 PubMedCrossRefGoogle Scholar
  30. 30.
    Silva R, Carmo H, Vilas-Boas V, Barbosa DJ, Palmeira A, Sousa E, Carvalho F, de Lourdes Bastos M et al (2014) Colchicine effect on P-glycoprotein expression and activity: in silico and in vitro studies. Chem Biol Interact 218:50–62. doi:10.1016/j.cbi.2014.04.009
  31. 31.
    Kathawala RJ, Chen J-J, Zhang Y-K, Wang Y-J, Patel A, Wang D-S, Talele TT, Ashby CR et al (2014) Masitinib antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance. Int J Oncol 44:1634–1642. doi:10.3892/ijo.2014.2341 PubMedPubMedCentralGoogle Scholar
  32. 32.
    Dwivedi GR, Upadhyay HC, Yadav DK, Singh V, Srivastava SK, Khan F, Darmwal NS, Darokar MP (2014) 4‐Hydroxy‐α‐tetralone and its derivative as drug resistance reversal agents in multi drug resistant Escherichia coli. Chem Biol Drug Des 83:482–492. doi:10.1111/cbdd.12263 PubMedCrossRefGoogle Scholar
  33. 33.
    Tajima Y, Nakagawa H, Tamura A, Kadioglu O, Satake K, Mitani Y, Murase H, Regasini LO et al (2014) Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1. Phytomedicine 21:323–332. doi:10.1016/j.phymed.2013.08.024 PubMedCrossRefGoogle Scholar
  34. 34.
    Tan W, Mei H, Chao L, Liu T, Pan X, Shu M, Yang L (2013) Combined QSAR and molecule docking studies on predicting P-glycoprotein inhibitors. J Comput Aided Mol Des 27:1067–1073. doi:10.1007/s10822-013-9697-8 PubMedCrossRefGoogle Scholar
  35. 35.
    Ferreira RJ, Ferreira M-JU, dos Santos DJ (2013) Molecular docking characterizes substrate-binding sites and efflux modulation mechanisms within P-glycoprotein. J Chem Inf Model 53:1747–1760. doi:10.1021/ci400195v PubMedCrossRefGoogle Scholar
  36. 36.
    Tiwari AK, Sodani K, C-l D, Abuznait AH, Singh S, Xiao Z-J, Patel A, Talele TT et al (2013) Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft models. Cancer Lett 328:307–317. doi:10.1016/j.canlet.2012.10.001 PubMedCrossRefGoogle Scholar
  37. 37.
    Chufan EE, Kapoor K, Sim H-M, Singh S, Talele TT, Durell SR, Ambudkar SV (2013) Multiple transport-active binding sites are available for a single substrate on human P-glycoprotein (ABCB1). PLoS One 8:e82463. doi:10.1371/journal.pone.0082463 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kanaoka S, Kimura Y, Fujikawa M, Nakagawa Y, Ueda K, Akamatsu M (2013) Substrate recognition by P-glycoprotein efflux transporters: structure-ATPase activity relationship of diverse chemicals and agrochemicals. J Pest Sci 38:112–122. doi:10.1584/jpestics.D13-022 CrossRefGoogle Scholar
  39. 39.
    Zhang D-M, Shu C, Chen J-J, Sodani K, Wang J, Bhatnagar J, Lan P, Ruan Z-X et al (2012) BBA, a derivative of 23-hydroxybetulinic acid, potently reverses ABCB1-mediated drug resistance in vitro and in vivo. Mol Pharm 9:3147–3159. doi:10.1021/mp300249s
  40. 40.
    Dolghih E, Bryant C, Renslo AR, Jacobson MP (2011) Predicting binding to P-glycoprotein by flexible receptor docking. PLoS Comput Biol 7:e1002083. doi:10.1371/journal.pcbi.1002083
  41. 41.
    Kalia NP, Mahajan P, Mehra R, Nargotra A, Sharma JP, Koul S, Khan IA (2012) Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. J Antimicrob Chemother 67:2401–2408. doi:10.1093/jac/dks232 PubMedCrossRefGoogle Scholar
  42. 42.
    Xiao Z-P, Wang X-D, Wang P-F, Zhou Y, Zhang J-W, Zhang L, Zhou J, Zhou S-S et al (2014) Design, synthesis, and evaluation of novel fluoroquinolone–flavonoid hybrids as potent antibiotics against drug-resistant microorganisms. Eur J Med Chem 80:92–100. doi:10.1016/j.ejmech.2014.04.037 PubMedCrossRefGoogle Scholar
  43. 43.
    George AM (1996) Multidrug resistance in enteric and other Gram-negative bacteria. FEMS Microbiol Lett 139:1–10. doi:10.1111/j.1574-6968.1996.tb08172.x PubMedCrossRefGoogle Scholar
  44. 44.
    Pagès J-M, Amaral L (2009) Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria. Biochim Biophys Acta 1794:826–833. doi:10.1016/j.bbapap.2008.12.011 PubMedCrossRefGoogle Scholar
  45. 45.
    Upadhyay R (2011) Emergence of drug resistance in microbes, its dissemination and target modification of antibiotics: a life threatening problem to human society. Int J Pharm Biol Res 2:119–126Google Scholar
  46. 46.
    Utsui Y, Yokota T (1985) Role of an altered penicillin-binding protein in methicillin-and cephem-resistant Staphylococcus aureus. Antimicrob Agents Chemother 28:397–403. doi:10.1128/AAC.28.3.397 PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Sapunaric FM, Aldema-Ramos M, McMurry LM (2005) Tetracycline resistance: efflux, mutation, and other mechanisms. In: White DG, Alekshun MN, McDermot PF (eds) Frontiers in antimicrobial resistance, a tribute to Stuart B. Levy. ASM Press, Washington, DC, pp 3–18CrossRefGoogle Scholar
  49. 49.
    Ruggerone P, Murakami S, Pos KM, Vargiu AV (2013) RND efflux pumps: structural information translated into function and inhibition mechanisms. Curr Top Med Chem 13:3079–3100. doi:10.2174/15680266113136660220 PubMedCrossRefGoogle Scholar
  50. 50.
    Blair JM, Bavro VN, Ricci V, Modi N, Cacciotto P, Kleinekathfer U, Ruggerone P, Vargiu AV et al (2015) AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. Proc Natl Acad Sci U S A 112:3511–3516. doi:10.1073/pnas.1419939112 PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Piddock LJ (2006) Multidrug-resistance efflux pumps – not just for resistance. Nat Rev Microbiol 4:629–636. doi:10.1038/nrmicro1464 PubMedCrossRefGoogle Scholar
  52. 52.
    Rosner JL, Martin RG (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 PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Guelfo JR, Rodriguez-Rojas A, Matic I, Blazquez J (2010) A MATE-family efflux pump rescues the Escherichia coli 8-oxoguanine-repair-deficient mutator phenotype and protects against H2O2 killing. PLoS Genet 6:e1000931. doi:10.1371/journal.pgen.1000931 PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bogomolnaya LM, Andrews KD, Talamantes M, Maple A, Ragoza Y, Vazquez-Torres A, Andrews-Polymenis H (2013) The ABC-type efflux pump MacAB protects Salmonella enterica serovar Typhimurium from oxidative stress. mBio 4:e00630-13. doi:10.1128/mBio.00630-13
  56. 56.
    Poole K (2012) Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. Trends Microbiol 20:227–234. doi:10.1016/j.tim.2012.02.004 PubMedCrossRefGoogle Scholar
  57. 57.
    Podnecky NL, Rhodes KA, Schweizer HP (2015) Efflux pump-mediated drug resistance in Burkholderia. Front Microbiol 6:305. doi:10.3389/fmicb.2015.00305
  58. 58.
    Baugh S, Phillips CR, Ekanayaka AS, Piddock LJ, Webber MA (2014) Inhibition of multidrug efflux as a strategy to prevent biofilm formation. J Antimicrob Chemother 69:673–681. doi:10.1093/jac/dkt420 PubMedCrossRefGoogle Scholar
  59. 59.
    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 PubMedCrossRefGoogle Scholar
  60. 60.
    Saier MH Jr, Reddy VS, Tamang DG, Vastermark A (2014) The transporter classification database. Nucleic Acids Res 42:D251–D258. doi:10.1093/nar/gkt1097 PubMedCrossRefGoogle Scholar
  61. 61.
    Ren Q, Chen K, Paulsen IT (2007) TransportDB: a comprehensive database resource for cytoplasmic membrane transport systems and outer membrane channels. Nucleic Acids Res 35:D274–D279. doi:10.1093/nar/gkl925 PubMedCrossRefGoogle Scholar
  62. 62.
    Eswaran J, Koronakis E, Higgins MK, Hughes C, Koronakis V (2004) Three’s company: component structures bring a closer view of tripartite drug efflux pumps. Curr Opin Struct Biol 14:741–747. doi:10.1016/j.sbi.2004.10.003 PubMedCrossRefGoogle Scholar
  63. 63.
    Du D, van Veen HW, Murakami S, Pos KM, Luisi BF (2015) Structure, mechanism and cooperation of bacterial multidrug transporters. Curr Opin Struct Biol 33:76–91. doi:10.1016/j.sbi.2015.07.015 PubMedCrossRefGoogle Scholar
  64. 64.
    Higgins CF (2001) ABC transporters: physiology, structure and mechanism – an overview. Res Microbiol 152:205–210. doi:10.1016/S0923-2508(01)01193-7 PubMedCrossRefGoogle Scholar
  65. 65.
    Shapiro AB, Fox K, Lam P, Ling V (1999) Stimulation of P‐glycoprotein‐mediated drug transport by prazosin and progesterone. Eur J Biochem 259:841–850. doi:10.1046/j.1432-1327.1999.00098.x PubMedCrossRefGoogle Scholar
  66. 66.
    Martin C, Berridge G, Higgins CF, Mistry P, Charlton P, Callaghan R (2000) Communication between multiple drug binding sites on P-glycoprotein. Mol Pharmacol 58:624–632. doi:10.1124/mol.58.3.624 PubMedGoogle Scholar
  67. 67.
    Higgins CF, Linton KJ (2004) The ATP switch model for ABC transporters. Nat Struct Mol Biol 11:918–926. doi:10.1038/nsmb836 PubMedCrossRefGoogle Scholar
  68. 68.
    Lu M, Symersky J, Radchenko M, Koide A, Guo Y, Nie R, Koide S (2013) Structures of a Na+-coupled, substrate-bound MATE multidrug transporter. Proc Natl Acad Sci U S A 110:2099–2104. doi:10.1073/pnas.1219901110 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Schuldiner S (2012) Undecided membrane proteins insert in random topologies. Up, down and sideways: it does not really matter. Trends Biochem Sci 37:215–219. doi:10.1016/j.tibs.2012.02.006 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Martin C, Berridge G, Mistry P, Higgins C, Charlton P, Callaghan R (2000) Drug binding sites on P-glycoprotein are altered by ATP binding prior to nucleotide hydrolysis. Biochemistry 39:11901–11906. doi:10.1021/bi000559b PubMedCrossRefGoogle Scholar
  71. 71.
    McDevitt CA, Crowley E, Hobbs G, Starr KJ, Kerr ID, Callaghan R (2008) Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2? FEBS J 275:4354–4362. doi:10.1111/j.1742-4658.2008.06578.x PubMedCrossRefGoogle Scholar
  72. 72.
    Yan N (2013) Structural advances for the major facilitator superfamily (MFS) transporters. Trends Biochem Sci 38:151–159. doi:10.1016/j.tibs.2013.01.003 PubMedCrossRefGoogle Scholar
  73. 73.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Lewinson O, Adler J, Sigal N, Bibi E (2006) Promiscuity in multidrug recognition and transport: the bacterial MFS Mdr transporters. Mol Microbiol 61:277–284. doi:10.1111/j.1365-2958.2006.05254.x PubMedCrossRefGoogle Scholar
  76. 76.
    Fluman N, Ryan CM, Whitelegge JP, Bibi E (2012) Dissection of mechanistic principles of a secondary multidrug efflux protein. Mol Cell 47:777–787. doi:10.1016/j.molcel.2012.06.018 PubMedCrossRefGoogle Scholar
  77. 77.
    Nikaido H, Zgurskaya HI (1999) Antibiotic efflux mechanisms. Curr Opin Infect Dis 12:529–536PubMedCrossRefGoogle Scholar
  78. 78.
    Kuroda T, Tsuchiya T (2009) Multidrug efflux transporters in the MATE family. Biochim Biophys Acta 1794:763–768. doi:10.1016/j.bbapap.2008.11.012 PubMedCrossRefGoogle Scholar
  79. 79.
    He X, Szewczyk P, Karyakin A, Evin M, Hong WX, Zhang Q, Chang G (2010) Structure of a cation-bound multidrug and toxic compound extrusion transporter. Nature 467:991–994. doi:10.1038/nature09408 PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Tanaka Y, Hipolito CJ, Maturana AD, Ito K, Kuroda T, Higuchi T, Katoh T, Kato HE et al (2013) Structural basis for the drug extrusion mechanism by a MATE multidrug transporter. Nature 496:247–251. doi:10.1038/nature12014 PubMedCrossRefGoogle Scholar
  81. 81.
    Paulsen IT, Skurray RA, Tam R, Saier MH Jr, Turner RJ, Weiner JH, Goldberg EB, Grinius LL (1996) The SMR family: a novel family of multidrug efflux proteins involved with the efflux of lipophilic drugs. Mol Microbiol 19:1167–1175. doi:10.1111/j.1365-2958.1996.tb02462.x PubMedCrossRefGoogle Scholar
  82. 82.
    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 PubMedCrossRefGoogle Scholar
  83. 83.
    Pornillos O, Chen Y-J, Chen AP, Chang G (2005) X-ray structure of the EmrE multidrug transporter in complex with a substrate. Science 310:1950–1953. doi:10.1126/science.1119776 PubMedCrossRefGoogle Scholar
  84. 84.
    Chen YJ, Pornillos O, Lieu S, Ma C, Chen AP, Chang G (2007) X-ray structure of EmrE supports dual topology model. Proc Natl Acad Sci U S A 104:18999–19004. doi:10.1073/pnas.0709387104 PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Korkhov VM, Tate CG (2008) Electron crystallography reveals plasticity within the drug binding site of the small multidrug transporter EmrE. J Mol Biol 377:1094–1103. doi:10.1016/j.jmb.2008.01.056 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Morrison EA, DeKoster GT, Dutta S, Vafabakhsh R, Clarkson MW, Bahl A, Kern D, Ha T et al (2011) Antiparallel EmrE exports drugs by exchanging between asymmetric structures. Nature 481:45–50. doi:10.1038/nature10703 PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Rotem D, Schuldiner S (2004) EmrE, a multidrug transporter from Escherichia coli, transports monovalent and divalent substrates with the same stoichiometry. J Biol Chem 279:48787–48793. doi:10.1074/jbc.M408187200 PubMedCrossRefGoogle Scholar
  88. 88.
    Venter H, Mowla R, Ohene-Agyei T, Ma S (2015) RND-type drug efflux pumps from Gram-negative bacteria: molecular mechanism and inhibition. Front Microbiol 6:377. doi:10.3389/fmicb.2015.00377 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Saier M, Tam R, Reizer A, Reizer J (1994) Two novel families of bacterial membrane proteins concerned with nodulation, cell division and transport. Mol Microbiol 11:841–847. doi:10.1111/j.1365-2958.1994.tb00362.x PubMedCrossRefGoogle Scholar
  90. 90.
    Nikaido H (1996) Multidrug efflux pumps of Gram-negative bacteria. J Bacteriol 178:5853–5859PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Dreier J, Ruggerone P (2015) Interaction of antibacterial compounds with RND efflux pumps in Pseudomonas aeruginosa. Front Microbiol 6:660. doi:10.3389/fmicb.2015.00660 PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Symmons MF, Bokma E, Koronakis E, Hughes C, 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 PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Murakami S, Nakashima R, Yamashita E, Yamaguchi A (2002) Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419:587–593. doi:10.1038/nature01050 PubMedCrossRefGoogle Scholar
  97. 97.
    Sennhauser G, Bukowska MA, Briand C, Grutter MG (2009) Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. J Mol Biol 389:134–145. doi:10.1016/j.jmb.2009.04.001 PubMedCrossRefGoogle Scholar
  98. 98.
    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. doi:10.1038/nature05076 PubMedCrossRefGoogle Scholar
  99. 99.
    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. doi:10.1038/nature10641 PubMedGoogle Scholar
  100. 100.
    Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT et al (2009) Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323:1718–1722. doi:10.1126/science.1168750 PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Jara GE, Vera DMA, Pierini AB (2013) Binding of modulators to mouse and human multidrug resistance P-glycoprotein. A computational study. J Mol Graph Model 46:10–21. doi:10.1016/j.jmgm.2013.09.001 PubMedCrossRefGoogle Scholar
  102. 102.
    Wise JG (2012) Catalytic transitions in the human MDR1 P-glycoprotein drug binding sites. Biochemistry 51:5125–5141. doi:10.1021/bi300299z PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Gadhe CC, Kothandan G, Joo Cho S (2013) In silico study of desmosdumotin as an anticancer agent: homology modeling, docking and molecular dynamics simulation approach. Anti-Cancer Agents Med Chem 13:1636–1644. doi:10.2174/18715206113139990302 CrossRefGoogle Scholar
  104. 104.
    Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, Pos KM (2006) Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313:1295–1298. doi:10.1126/science.1131542 PubMedCrossRefGoogle Scholar
  105. 105.
    Seeger MA, Diederichs K, Eicher T, Brandstatter L, Schiefner A, Verrey F, Pos KM (2008) The AcrB efflux pump: conformational cycling and peristalsis lead to multidrug resistance. Curr Drug Targets 9:729–749. doi:10.2174/138945008785747789 PubMedCrossRefGoogle Scholar
  106. 106.
    Murakami S (2008) Multidrug efflux transporter, AcrB – the pumping mechanism. Curr Opin Struct Biol 18:459–465. doi:10.1016/j.sbi.2008.06.007 PubMedCrossRefGoogle Scholar
  107. 107.
    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. doi:10.1038/nature10641
  108. 108.
    Eicher T, Cha HJ, Seeger MA, Brandstatter L, El-Delik J, Bohnert JA, Kern WV, Verrey F et al (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 U S A 109:5687–5692. doi:10.1073/pnas.1114944109 PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Pos KM (2009) Drug transport mechanism of the AcrB efflux pump. Biochim Biophys Acta 1794:782–793. doi:10.1016/j.bbapap.2008.12.015 PubMedCrossRefGoogle Scholar
  110. 110.
    Nikaido H, Basina M, Nguyen V, Rosenberg EY (1998) Multidrug efflux pump AcrAB of Salmonella typhimurium excretes only those β-lactam antibiotics containing lipophilic side chains. J Bacteriol 180:4686–4692PubMedPubMedCentralGoogle Scholar
  111. 111.
    Husain F, Bikhchandani M, 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 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Wong K, Ma J, Rothnie A, Biggin PC, Kerr ID (2014) Towards understanding promiscuity in multidrug efflux pumps. Trends Biochem Sci 39:8–16. doi:10.1016/j.tibs.2013.11.002 PubMedCrossRefGoogle Scholar
  113. 113.
    Zechini B, Versace I (2009) Inhibitors of multidrug resistant efflux systems in bacteria. Recent Pat Antiinfect Drug Discov 4:37–50. doi:10.2174/157489109787236256 PubMedCrossRefGoogle Scholar
  114. 114.
    Sun J, Deng Z, Yan A (2014) Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun 453:254–267. doi:10.1016/j.bbrc.2014.05.090 PubMedCrossRefGoogle Scholar
  115. 115.
    Hirakata Y, Kondo A, Hoshino K, Yano H, Arai K, Hirotani A, Kunishima H, Yamamoto N et al (2009) Efflux pump inhibitors reduce the invasiveness of Pseudomonas aeruginosa. Int J Antimicrob Agents 34:343–346. doi:10.1016/j.ijantimicag.2009.06.007 PubMedCrossRefGoogle Scholar
  116. 116.
    Bhardwaj AK, Mohanty P (2012) Bacterial efflux pumps involved in multidrug resistance and their inhibitors: rejuvinating the antimicrobial chemotherapy. Recent Pat Antiinfect Drug Discov 7:73–89. doi:10.2174/157489112799829710 PubMedCrossRefGoogle Scholar
  117. 117.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Wilke MS, Heller M, Creagh AL, Haynes CA, McIntosh LP, Poole K, Strynadka NC (2008) The crystal structure of MexR from Pseudomonas aeruginosa in complex with its antirepressor ArmR. Proc Natl Acad Sci U S A 105:14832–14837. doi:10.1073/pnas.0805489105 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Starr LM, Fruci M, Poole K (2012) Pentachlorophenol induction of the Pseudomonas aeruginosa mexAB-oprM efflux operon: involvement of repressors NalC and MexR and the antirepressor ArmR. PLoS One 7:e32684. doi:10.1371/journal.pone.0032684 PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Hay T, Fraud S, Lau CH, Gilmour C, Poole K (2013) Antibiotic inducibility of the mexXY multidrug efflux operon of Pseudomonas aeruginosa: involvement of the MexZ anti-repressor ArmZ. PLoS One 8:e56858. doi:10.1371/journal.pone.0056858 PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Purssell A, Poole K (2013) Functional characterization of the NfxB repressor of the mexCD-oprJ multidrug efflux operon of Pseudomonas aeruginosa. Microbiology 159:2058–2073. doi:10.1099/mic.0.069286-0 PubMedCrossRefGoogle Scholar
  122. 122.
    Lau CH, Hughes D, Poole K (2014) MexY-promoted aminoglycoside resistance in Pseudomonas aeruginosa: involvement of a putative proximal binding pocket in aminoglycoside recognition. mBio 5:e01068–14. doi:10.1128/mBio.01068-14
  123. 123.
    Lomovskaya O, Lewis K, Matin A (1995) EmrR is a negative regulator of the Escherichia coli multidrug resistance pump EmrAB. J Bacteriol 177:2328–2334PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Rice A, Liu Y, Michaelis ML, Himes RH, Georg GI, Audus KL (2005) Chemical modification of paclitaxel (Taxol) reduces P-glycoprotein interactions and increases permeation across the blood-brain barrier in vitro and in situ. J Med Chem 48:832–838. doi:10.1021/jm040114b
  125. 125.
    Chopra I (2002) New developments in tetracycline antibiotics: glycylcyclines and tetracycline efflux pump inhibitors. Drug Resist Updat 5:119–125. doi:10.1016/S1368-7646(02)00051-1
  126. 126.
    Chollet R, Chevalier J, Bryskier A, Pagès JM (2004) The AcrAB-TolC pump is involved in macrolide resistance but not in telithromycin efflux in Enterobacter aerogenes and Escherichia coli. Antimicrob Agents Chemother 48:3621–3624. doi:10.1128/AAC.48.9.3621-3624.2004 PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Hooper DC (2000) Mechanisms of action and resistance of older and newer fluoroquinolones. Clin Infect Dis 31(Suppl 2):S24–S28. doi:10.1086/314056 PubMedCrossRefGoogle Scholar
  128. 128.
    Pagès JM, Masi M, Barbe J (2005) Inhibitors of efflux pumps in Gram-negative bacteria. Trends Mol Med 11:382–389. doi:10.1016/j.molmed.2005.06.006 PubMedCrossRefGoogle Scholar
  129. 129.
    Marquez B (2005) Bacterial efflux systems and efflux pumps inhibitors. Biochimie 87:1137–1147. doi:10.1016/j.biochi.2005.04.012 PubMedCrossRefGoogle Scholar
  130. 130.
    Lynch AS (2006) Efflux systems in bacterial pathogens: an opportunity for therapeutic intervention? An industry view. Biochem Pharmacol 71:949–956. doi:10.1016/j.bcp.2005.10.021 PubMedCrossRefGoogle Scholar
  131. 131.
    Mahamoud A, Chevalier J, Alibert-Franco S, Kern WV, Pagès J-M (2007) Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J Antimicrob Chemother 59:1223–1229. doi:10.1093/jac/dkl493 PubMedCrossRefGoogle Scholar
  132. 132.
    Nakashima R, Sakurai K, Yamasaki S, Hayashi K, Nagata C, Hoshino K, Onodera Y, Nishino K et al (2013) Structural basis for the inhibition of bacterial multidrug exporters. Nature 500:102–106. doi:10.1038/nature12300 PubMedCrossRefGoogle Scholar
  133. 133.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Nguyen ST, Kwasny SM, Ding X, Cardinale SC, McCarthy CT, Kim H-S, Nikaido H, Peet NP et al (2015) Structure–activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors. Bioorg Med Chem 23:2024–2034. doi:10.1016/j.bmc.2015.03.016 PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Opperman TJ, Nguyen ST (2015) Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol 6:421. doi:10.3389/fmicb.2015.00421 PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Martins M, Dastidar SG, Fanning S, Kristiansen JE, Molnar J, Pagès JM, Schelz Z, Spengler G et al (2008) Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: mechanisms for their direct and indirect activities. Int J Antimicrob Agents 31:198–208. doi:10.1016/j.ijantimicag.2007.10.025
  138. 138.
    Li X-Z, Nikaido H (2004) Efflux-mediated drug resistance in bacteria. Drugs 64:159–204. doi:10.2165/00003495-200464020-00004 PubMedCrossRefGoogle Scholar
  139. 139.
    Kourtesi C, Ball AR, Huang Y-Y, Jachak SM, Vera DMA, Khondkar P, Gibbons S, Hamblin MR et al (2013) Microbial efflux systems and inhibitors: approaches to drug discovery and the challenge of clinical implementation. Open Microbiol J 7:34–52. doi:10.2174/1874285801307010034 PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Tikhonova EB, Yamada Y, Zgurskaya HI (2011) Sequential mechanism of assembly of multidrug efflux pump AcrAB-TolC. Chem Biol 18:454–463. doi:10.1016/j.chembiol.2011.02.011 PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Zeng B, Wang H, Zou L, Zhang A, Yang X, Guan Z (2010) Evaluation and target validation of indole derivatives as inhibitors of the AcrAB-TolC efflux pump. Biosci Biotechnol Biochem 74:2237–2241. doi:10.1271/bbb.100433
  142. 142.
    Andersen C, Koronakis E, Hughes C, Koronakis V (2002) 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. doi:10.1046/j.1365-2958.2002.02898.x PubMedCrossRefGoogle Scholar
  143. 143.
    Chevalier J, Mulfinger C, Garnotel E, Nicolas P, Davin-Regli A, Pagès JM (2008) Identification and evolution of drug efflux pump in clinical Enterobacter aerogenes strains isolated in 1995 and 2003. PLoS One 3:e3203. doi:10.1371/journal.pone.0003203 PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Yamaguchi A, Nakashima R, Sakurai K (2015) Structural basis of RND-type multidrug exporters. Front Microbiol 6:327. doi:10.3389/fmicb.2015.00327 PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Du D, van Veen HW, Luisi BF (2015) Assembly and operation of bacterial tripartite multidrug efflux pumps. Trends Microbiol 23:311–319. doi:10.1016/j.tim.2015.01.010 PubMedCrossRefGoogle Scholar
  146. 146.
    Van Bambeke F, Lee VJ (2006) Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent Pat Antiinfect Drug Discov 1:157–175. doi:10.2174/157489106777452692
  147. 147.
    Schwede T, Peitsch M (2008) Computational structural biology: methods and applications. World Scientific Publishing Co. Pte. Ltd., SingaporeCrossRefGoogle Scholar
  148. 148.
    Halperin I, Ma B, Wolfson H, Nussinov R (2002) Principles of docking: an overview of search algorithms and a guide to scoring functions. Proteins 47:409–443. doi:10.1002/prot.10115 PubMedCrossRefGoogle Scholar
  149. 149.
    van Dijk AD, Boelens R, Bonvin AM (2005) Data‐driven docking for the study of biomolecular complexes. FEBS J 272:293–312. doi:10.1111/j.1742-4658.2004.04473.x PubMedCrossRefGoogle Scholar
  150. 150.
    van Dijk AD, Bonvin AM (2006) Solvated docking: introducing water into the modelling of biomolecular complexes. Bioinformatics 22:2340–2347. doi:10.1093/bioinformatics/btl395 PubMedCrossRefGoogle Scholar
  151. 151.
    Martí-Renom MA, Stuart AC, Fiser A, Sánchez R, Melo F, Šali A (2000) Comparative protein structure modeling of genes and genomes. Ann Rev Biophys Biomol Struct 29:291–325. doi:10.1146/annurev.biophys.29.1.291 CrossRefGoogle Scholar
  152. 152.
    Šali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779–815. doi:10.1006/jmbi.1993.1626 PubMedCrossRefGoogle Scholar
  153. 153.
    Eswar N, Webb B, Marti‐Renom MA, Madhusudhan M, Eramian D, Shen M, Pieper U, Sali A (2006) Comparative protein structure modeling using Modeller. Curr Protoc Bioinformatics 15:5.6.1–5.6.30. doi:10.1002/0471250953.bi0506s15 CrossRefGoogle Scholar
  154. 154.
    Salam NK, Nuti R, Sherman W (2009) Novel method for generating structure-based pharmacophores using energetic analysis. J Chem Inf Model 49:2356–2368. doi:10.1021/ci900212v PubMedCrossRefGoogle Scholar
  155. 155.
    Joseph-McCarthy D (1999) Computational approaches to structure-based ligand design. Pharmacol Ther 84:179–191. doi:10.1016/S0163-7258(99)00031-5 PubMedCrossRefGoogle Scholar
  156. 156.
    Lyne PD (2002) Structure-based virtual screening: an overview. Drug Discov Today 7:1047–1055. doi:10.1016/S1359-6446(02)02483-2 PubMedCrossRefGoogle Scholar
  157. 157.
    Galeazzi R (2009) Molecular dynamics as a tool in rational drug design: current status and some major applications. Curr Comput Aided Drug Des 5:225–240. doi:10.2174/157340909789577847 CrossRefGoogle Scholar
  158. 158.
    Ferreira RJ, Ferreira M-JU, dos Santos DJ (2012) Insights on P-glycoprotein’s efflux mechanism obtained by molecular dynamics simulations. J Chem Theory Comput 8:1853–1864. doi:10.1021/ct300083m PubMedCrossRefGoogle Scholar
  159. 159.
    Ruggerone P, Vargiu AV, Collu F, Fischer N, Kandt C (2013) Molecular dynamics computer simulations of multidrug RND efflux pumps. Comput Struct Biotechnol J 5:e201302008. doi:10.5936/csbj.201302008 PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Schlitter J, Engels M, Krüger P (1994) Targeted molecular dynamics: a new approach for searching pathways of conformational transitions. J Mol Graph 12:84–89. doi:10.1016/0263-7855(94)80072-3 PubMedCrossRefGoogle Scholar
  161. 161.
    Izvekov S, Voth GA (2005) A multiscale coarse-graining method for biomolecular systems. J Phys Chem B 109:2469–2473. doi:10.1021/jp044629q PubMedCrossRefGoogle Scholar
  162. 162.
    Takada S (2012) Coarse-grained molecular simulations of large biomolecules. Curr Opin Struct Biol 22:130–137. doi:10.1016/j.sbi.2012.01.010 PubMedCrossRefGoogle Scholar
  163. 163.
    Parkin J, Chavent M, Khalid S (2015) Molecular simulations of Gram-negative bacterial membranes: a vignette of some recent successes. Biophys J 109:461–468. doi:10.1016/j.bpj.2015.06.050 PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Collu F, Cascella M (2013) Multidrug resistance and efflux pumps: insights from molecular dynamics simulations. Curr Top Med Chem 13:3165–3183. doi:10.2174/15680266113136660224 PubMedCrossRefGoogle Scholar
  165. 165.
    Ohene‐Agyei T, Mowla R, Rahman T, Venter H (2014) Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump. Microbiol Open 3:885–896. doi:10.1002/mbo3.212 CrossRefGoogle Scholar
  166. 166.
    Aparna V, Dineshkumar K, Mohanalakshmi N, Velmurugan D, Hopper W (2014) Identification of natural compound inhibitors for multidrug efflux pumps of Escherichia coli and Pseudomonas aeruginosa using in silico high-throughput virtual screening and in vitro validation. PLoS One 9:e101840. doi:10.1371/journal.pone.0101840
  167. 167.
    Takatsuka Y, Chen C, Nikaido H (2010) Mechanism of recognition of compounds of diverse structures by the multidrug efflux pump AcrB of Escherichia coli. Proc Natl Acad Sci U S A 107:6559–6565. doi:10.1073/pnas.1001460107 PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Vargiu AV, Nikaido H (2012) Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Natl Acad Sci U S A 109:20637–20642. doi:10.1073/pnas.1218348109 PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Vargiu AV, Ruggerone P, Opperman TJ, Nguyen ST, 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 PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    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. doi:10.1039/c2mb25184a PubMedCrossRefGoogle Scholar
  171. 171.
    Vargiu AV, Collu F, Schulz R, Pos KM, 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. doi:10.1021/ja202666x PubMedCrossRefGoogle Scholar
  172. 172.
    Bohnert JA, Schuster S, Seeger MA, Fahnrich E, Pos KM, Kern WV (2008) Site-directed mutagenesis reveals putative substrate binding residues in the Escherichia coli RND efflux pump AcrB. J Bacteriol 190:8225–8229. doi:10.1128/JB.00912-08 PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Sjuts H, Vargiu AV, Kwasny SM, Nguyen ST, Kim H-S, Ding X, Ornik AR, Ruggerone P et al (2016) Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proc Natl Acad Sci U S A 113:3509–3514. doi:10.1073/pnas.1602472113
  174. 174.
    Yilmaz S, Altinkanat-Gelmez G, Bolelli K, Guneser-Merdan D, Ufuk Over-Hasdemir M, Aki-Yalcin E, Yalcin I (2015) Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli. SAR QSAR Environ Res 26:853–871. doi:10.1080/1062936X.2015.1106581 PubMedCrossRefGoogle Scholar
  175. 175.
    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 PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    van Veen HW, Venema K, Bolhuis H, Oussenko I, Kok J, Poolman B, Driessen AJ, Konings WN (1996) Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR1. Proc Natl Acad Sci U S A 93:10668–10672PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    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 PubMedCrossRefGoogle Scholar
  178. 178.
    Davidson AL, Dassa E, Orelle C, Chen J (2008) Structure, function, and evolution of bacterial ATP-binding cassette systems. Microbiol Mol Biol Rev 72:317–364. doi:10.1128/MMBR.00031-07 PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Vandevuer S, Van Bambeke F, Tulkens PM, Prévost M (2006) Predicting the three‐dimensional structure of human P‐glycoprotein in absence of ATP by computational techniques embodying crosslinking data: insight into the mechanism of ligand migration and binding sites. Proteins 63:466–478. doi:10.1002/prot.20892 PubMedCrossRefGoogle Scholar
  180. 180.
    Pajeva IK, Wiese M (2002) Pharmacophore model of drugs involved in P-glycoprotein multidrug resistance: explanation of structural variety (hypothesis). J Med Chem 45:5671–5686. doi:10.1021/jm020941h PubMedCrossRefGoogle Scholar
  181. 181.
    Klepsch F, Chiba P, Ecker GF (2011) Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein. PLoS Comput Biol 7:e1002036. doi:10.1371/journal.pcbi.1002036 PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Liu M, Hou T, Feng Z, Li Y (2013) The flexibility of P-glycoprotein for its poly-specific drug binding from molecular dynamics simulations. J Biomol Struct Dyn 31:612–629. doi:10.1080/07391102.2012.706079 PubMedCrossRefGoogle Scholar
  183. 183.
    Ma J, Biggin PC (2013) Substrate versus inhibitor dynamics of P‐glycoprotein. Proteins 81:1653–1668. doi:10.1002/prot.24324 PubMedCrossRefGoogle Scholar
  184. 184.
    Dawson RJP, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443:180–185. doi:10.1038/nature05155 PubMedCrossRefGoogle Scholar
  185. 185.
    Prajapati R, Sangamwar AT (2014) Translocation mechanism of P-glycoprotein and conformational changes occurring at drug-binding site: insights from multi-targeted molecular dynamics. Biochim Biophys Acta 1838:2882–2898. doi:10.1016/j.bbamem.2014.07.018 PubMedCrossRefGoogle Scholar
  186. 186.
    Tardia P, Stefanachi A, Niso M, Stolfa DA, Mangiatordi GF, Alberga D, Nicolotti O, Lattanzi G et al (2014) Trimethoxybenzanilide-based P-glycoprotein modulators: an interesting case of lipophilicity tuning by intramolecular hydrogen bonding. J Med Chem 57:6403–6418. doi:10.1021/jm500697c PubMedCrossRefGoogle Scholar
  187. 187.
    Singh S, Mandlik V (2015) Structure based investigation on the binding interaction of transport proteins in leishmaniasis: insights from molecular simulation. Mol Biol Syst 11:1251–1259. doi:10.1039/c4mb00713a Google Scholar
  188. 188.
    Tomkiewicz D, Casadei G, Larkins-Ford J, Moy TI, Garner J, Bremner JB, Ausubel FM, Lewis K et al (2010) Berberine-INF55 (5-nitro-2-phenylindole) hybrid antimicrobials: effects of varying the relative orientation of the berberine and INF55 components. Antimicrob Agents Chemother 54:3219–3224. doi:10.1128/AAC.01715-09 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Venkata Krishnan Ramaswamy
    • 1
  • Pierpaolo Cacciotto
    • 1
  • Giuliano Malloci
    • 1
  • Paolo Ruggerone
    • 1
  • Attilio V. Vargiu
    • 1
  1. 1.Department of PhysicsUniversity of CagliariCagliariItaly

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