Efflux Pump Inhibitors and Their Role in the Reversal of Drug Resistance

  • Samreen
  • Iqbal Ahmad
  • Faizan Abul Qais
  • Meenu Maheshwari
  • Kendra P. Rumbaugh


The worldwide emergence of resistant bacteria to multiple antimicrobial drugs is one of the greatest hurdles to chemotherapy. Multidrug resistance (MDR) is the capability of pathogenic bacteria to survive lethal doses of antimicrobial drugs. One of the underlying mechanisms of survival under stressful conditions is the extrusion of drugs through membrane-embedded efflux proteins. These ubiquitous resistance elements, which confer resistance or cross resistance to multiple drugs, are considered MDR efflux transporters. Consequently, efflux pump inhibitors (EPIs) from various natural and synthetic sources have been developed to increase the therapeutic armamentarium for combating bacterial resistance and restoring the antibiotic activity. Owing to less toxicity issues than chemical-based EPIs, plant-based EPIs are gaining much importance, but none are yet undergoing clinical trials. In this review, we will introduce the concept of efflux pumps and their diversity and then provide a comprehensive understanding of efflux pump inhibitors from both plant and chemical sources, their mode of action and the recent advances in their development.


Multiple resistance Efflux pumps RND transporters EPI 



Samreen is thankful to UGC, New Delhi, for providing Non-Net Fellowship.


  1. Abreu, A. C., McBain, A. J., & Simoes, M. (2012). Plants as sources of new antimicrobials and resistance-modifying agents. Natural Product Reports, 29(9), 1007–1021.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Aghayan, S. S., Mogadam, H. K., Fazli, M., et al. (2017). The effects of berberine and palmatine on efflux pumps inhibition with different gene patterns in Pseudomonas Aeruginosa isolated from burn infections. AJMB9, 9(1), 2.Google Scholar
  3. Ahmed, M. A., Borsch, C. M., Neyfakh, A. A., & Schuldiner, S. (1993, May 25). Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine. Journal of Biological Chemistry, 268(15), 11086–11089.Google Scholar
  4. Amaral, L., Spengler, G., Martins, A., Armada, A., Handzlik, J., Kiec-Kononowicz, K., & Molnar, J. (2012). Inhibitors of bacterial efflux pumps that also inhibit efflux pumps of cancer cells. Anticancer Research, 32(7), 2947–2957.PubMedPubMedCentralGoogle Scholar
  5. Amaral, L., Martins, A., Spengler, G., & Molnar, J. (2014). Efflux pumps of gram-negative bacteria: What they do, how they do it, with what and how to deal with them. Frontiers in Pharmacology, 4, 168.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Anes, J., McCusker, M. P., Fanning, S., & Martins, M. (2015). The ins and outs of RND efflux pumps in Escherichia coli. Frontiers in Microbiology, 6, 587.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 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(7), 101840.CrossRefGoogle Scholar
  8. Avrain, L., Mertens, P., & Van Bambeke, F. (2013). RND efflux pumps in P. aeruginosa: An underestimated resistance mechanism. Antibiotic Susceptibility, 26321, 26–28.Google Scholar
  9. Aygül, A. (2015). The importance of efflux systems in antibiotic resistance and efflux pump inhibitors in the management of resistance. Mikrobiyoloji Bülteni, 49(2), 278–291.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Bag, A., & Chattopadhyay, R. R. (2014). Efflux-pump inhibitory activity of a gallotannin from Terminalia chebula fruit against multidrug-resistant uropathogenic Escherichia coli. Natural Product Research, 28(16), 1280–1283.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Barreto, H. M., Coelho, K. M., Ferreira, J. H., dos Santos, B. H., de Abreu, A. P., Coutinho, H. D., da Silva, R. A., de Sousa TO, Citó, A. M. D. G., & Lopes, J. A. (2016). Enhancement of the antibiotic activity of aminoglycosides by extracts from Anadenanthera colubrine (Vell.) Brenan var. cebil against multi-drug resistant bacteria. Natural Product Research, 30(11), 1289–1292.PubMedCrossRefPubMedCentralGoogle Scholar
  12. Bay, D. C., Rommens, K. L., & Turner, R. J. (2008). Small multidrug resistance proteins: A multidrug transporter family that continues to grow. Biochimica et Biophysica Acta, 1778(9), 1814–1838.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Beheshti, M., Talebi, M., Ardebili, A., Bahador, A., & Lari, A. R. (2014). Detection of AdeABC efflux pump genes in tetracycline-resistant Acinetobacter baumannii isolates from burn and ventilator-associated pneumonia patients. Journal of Pharmacy & Bioallied Sciences, 6(4), 229.CrossRefGoogle Scholar
  14. Berti, L., Lorenzi, V., Casanova, J., Muselli, A., Pagès, J.M. and Bolla, J.M. (2010) Geraniol as bacterial efflux pump inhibitor. European Patent No. EP 2 184 061 A1, 12 Jun 2010.Google Scholar
  15. Bhardwaj, A. K., & Mohanty, P. (2012). Bacterial efflux pumps involved in multidrug resistance and their inhibitors: Rejuvinating the antimicrobial chemotherapy. Recent Patents on Anti-Infective Drug Discovery, 7(1), 73–89.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Bhattacharyya, T., Sharma, A., Akhter, J., & Pathania, R. (2017). The small molecule IITR08027 restores the antibacterial activity of fluoroquinolones against multidrug-resistant Acinetobacter baumannii by efflux inhibition. International Journal of Antimicrobial Agents, 50(2), 219–226.PubMedCrossRefPubMedCentralGoogle Scholar
  17. Bialek-Davenet, S., Lavigne, J. P., Guyot, K., Mayer, N., Tournebize, R., Brisse, S., Leflon-Guibout, V., & Nicolas-Chanoine, M. H. (2014). Differential contribution of AcrAB and OqxAB efflux pumps to multidrug resistance and virulence in Klebsiella pneumoniae. The Journal of Antimicrobial Chemotherapy, 70(1), 81–88.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Blair, J. M., Richmond, G. E., & Piddock, L. J. (2014). Multidrug efflux pumps in gram-negative bacteria and their role in antibiotic resistance. Future Microbiology, 9(10), 1165–1177.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Blanco, P., Hernando-Amado, S., Reales-Calderon, J. A., Corona, F., Lira, F., Alcalde-Rico, M., Bernardini, A., Sanchez, M. B., & Martinez, J. L. (2016). Bacterial multidrug efflux pumps: Much more than antibiotic resistance determinants. Microorganism, 4(1), 14.CrossRefGoogle Scholar
  20. Bohnert, J. A., & Kern, W. V. (2005). Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrobial Agents and Chemotherapy, 49(2), 849–852.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Bohnert, J. A., Schuster, S., Kern, W. V., Karcz, T., Olejarz, A., Kaczor, A., Handzlik, J., & Kieć-Kononowicz, K. (2016). Novel piperazine arylideneimidazolones inhibit the AcrAB-TolC pump in Escherichia coli and simultaneously act as fluorescent membrane probes in a combined real-time influx and efflux assay. Antimicrobial Agents and Chemotherapy, 60(4), 1974–1983.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Boncoeur, E., Durmort, C., Bernay, B., Ebel, C., Di Guilmi, A. M., Croizé, J., Vernet, T., & Jault, J. M. (2012). PatA and PatB form a functional heterodimeric ABC multidrug efflux transporter responsible for the resistance of Streptococcus pneumoniae to fluoroquinolones. Biochemistry, 51(39), 7755–7765.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Bremner, J. B. (2007). Some approaches to new antibacterial agents. Pure and Applied Chemistry, 79(12), 2143–2153.CrossRefGoogle Scholar
  24. Chan, B. C., Han, X. Q., Lui, S. L., Wong, C. W., Wang, T. B., Cheung, D. W., Cheng, W., Ip, M., Han, S. Q., Yang, X. S., & Jolivalt, C. (2015). Combating against methicillin-resistant Staphylococcus aureus–two fatty acids from Purslane (Portulaca oleracea L.) exhibit synergistic effects with erythromycin. The Journal of Pharmacy and Pharmacology, 67(1), 107–116.PubMedCrossRefPubMedCentralGoogle Scholar
  25. Chevalier, J., Bredin, J., Mahamoud, A., Malléa, M., Barbe, J., & Pagès, J. M. (2004). Inhibitors of antibiotic efflux in resistant Enterobacter aerogenes and Klebsiella pneumoniae strains. Antimicrobial Agents and Chemotherapy, 48(3), 1043–1046.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Chitsaz, M., & Brown, M. H. (2017). The role played by drug efflux pumps in bacterial multidrug resistance. Essays in Biochemistry, 61(1), 127–139.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Choudhury, D., Talukdar, A. D., Choudhury, M. D., Maurya, A. P., Paul, D., Chanda, D., Chakravorty, A., & Bhattacharjee, A. (2015). Transcriptional analysis of MexAB-OprM efflux pumps system of Pseudomonas aeruginosa and its role in carbapenem resistance in a tertiary referral hospital in India. PLoS One, 10(7), 0133842.CrossRefGoogle Scholar
  28. Chovanová, R., Mezovská, J., Vaverková, Š., & Mikulášová, M. (2015). The inhibition the Tet (K) efflux pump of tetracycline resistant Staphylococcus epidermidis by essential oils from three Salvia species. Letters in Applied Microbiology, 61(1), 58–62.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Cox, D. (2015). Antibiotic resistance: The race to stop the silent tsunami facing modern medicine. The Guardian.Google Scholar
  30. Coyne, S., Courvalin, P., & Périchon, B. (2011). Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrobial Agents and Chemotherapy, 55(3), 947–953.PubMedCrossRefPubMedCentralGoogle Scholar
  31. Crow, A., Greene, N. P., Kaplan, E., & Koronakis, V. (2017). Structure and mechanotransmission mechanism of the MacB ABC transporter superfamily. Proceedings of the National Academy of Sciences, 114(47), 12572–12577.CrossRefGoogle Scholar
  32. Dantas, N., de Aquino, T. M., de Araújo-Júnior, J. X., da Silva-Júnior, E., Gomes, E., Gomes, A. A. S., Siqueira-Júnior, J. P., & Junior, F. J. B. M. (2018). Aminoguanidine hydrazones (AGH’s) as modulators of norfloxacin resistance in Staphylococcus aureus that overexpress NorA efflux pump. Chemico-Biological Interactions, 280, 8–14.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Daury, L., Orange, F., Taveau, J. C., Verchère, A., Monlezun, L., Gounou, C., Marreddy, R. K., Picard, M., Broutin, I., Pos, K. M., & Lambert, O. (2016). Tripartite assembly of RND multidrug efflux pumps. Nature Communications, 12(7), 1073.Google Scholar
  34. Davin-Regli, A., Masi, M., Bialek, S., Nicolas-Chanoine, M. H., & Pagès, J. M. (2016). Antimicrobial drug efflux pumps in Enterobacter and Klebsiella. In L. Xianzhi, C. A. Elkins, & H. I. Zgurskaya (Eds.), Efflux-mediated antimicrobial resistance in Bacteria (Ist ed.). Cham: Springer International Publishing.Google Scholar
  35. Dhanarani, S., Congeevaram, S., Piruthiviraj, P., Park, J. H., & Kaliannan, T. (2017). Inhibitory effects of reserpine against efflux pump activity of antibiotic resistance bacteria. Chemical Biology Letters, 4(2), 69–72.Google Scholar
  36. Dwivedi, G. R., Maurya, A., Yadav, D. K., Khan, F., Darokar, M. P., & Srivastava, S. K. (2015). Drug resistance reversal potential of Ursolic acid derivatives against Nalidixic acid-and multidrug-resistant Escherichia coli. Chemical Biology & Drug Design, 86(3), 272–283.CrossRefGoogle Scholar
  37. Eicher, T., Cha, H. J., Seeger, M. A., Brandstätter, L., El-Delik, J., Bohnert, J. A., Kern, W. V., Verrey, F., Grütter, 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. Proceedings of the National Academy of Sciences of the United States of America, 109, 5687–5692.Google Scholar
  38. El-Banna, T. E., Sonbol, F. I., El-Aziz, A. A., & Al-Fakharany, O. M. (2016). Modulation of antibiotic efficacy against Klebsiella pneumoniae by antihistaminic drugs. Journal of Medical Microbiology & Diagnosis, 5(225), 2161–0703.Google Scholar
  39. Fankam, A. G., Kuiate, J. R., & Kuete, V. (2017). Antibacterial and antibiotic resistance modulatory activities of leaves and bark extracts of Recinodindron heudelotii (Euphorbiaceae) against multidrug-resistant gram-negative bacteria. BMC Complementary and Alternative Medicine, 17(1), 168.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Ferreira, S., Silva, F., Queiroz, J. A., Oleastro, M., & Domingues, F. C. (2014). Resveratrol against Arcobacter butzleri and Arcobacter cryaerophilus: Activity and effect on cellular functions. Int J Food Microbiol, 180, 62–68.Google Scholar
  41. Foster, T. J. (2017). Antibiotic resistance in Staphylococcus aureus. Current status and future prospects. FEMS Microbiology Reviews, 1;41(3), 430–449.CrossRefGoogle Scholar
  42. Furi, L., Ciusa, M. L., Knight, D., Di Lorenzo, V., Tocci, N., Cirasola, D., Aragones, L., Coelho, J. R., Freitas, A. T., Marchi, E., & Moce, L. (2013). Evaluation of reduced susceptibility to quaternary ammonium compounds and bisbiguanides in clinical isolates and laboratory-generated mutants of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, 57(8), 3488–3497.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Garvey, M. I., & Piddock, L. J. (2008). The efflux pump inhibitor reserpine selects multidrug-resistant Streptococcus pneumoniae strains that overexpress the ABC transporters PatA and PatB. Antimicrobial Agents and Chemotherapy, 52(5), 1677–1685.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Goli HR, Nahaei MR, Rezaee MA, Hasani A, Kafil HS, Aghazadeh M, Nikbakht M and Khalili Y (2017) Role of MexAB-OprM and MexXY-OprM efflux pumps and class 1 integrons in resistance to antibiotics in burn and intensive care unit isolates of Pseudomonas aeruginosa. Journal Infect Public Health 11(3):364-372.PubMedCrossRefPubMedCentralGoogle Scholar
  45. Gottesman, M. M., & Ling, V. (2006). The molecular basis of multidrug resistance in cancer: The early years of P-glycoprotein research. FEBS Letters, 580(4), 998–1009.PubMedCrossRefPubMedCentralGoogle Scholar
  46. Guérin, F., Galimand, M., Tuambilangana, F., Courvalin, P., & Cattoir, V. (2014). Overexpression of the novel MATE fluoroquinolone efflux pump FepA in Listeria monocytogenes is driven by inactivation of its local repressor FepR. PLoS One, 9(9), 106340.CrossRefGoogle Scholar
  47. Hashimoto, K., Ogawa, W., Nishioka, T., Tsuchiya, T., & Kuroda, T. (2013). Functionally cloned pdrM from Streptococcus pneumoniae encodes a Na+ coupled multidrug efflux pump. PLoS One, 8(3), e59525.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hernando-Amado, S., Blanco, P., Alcalde-Rico, M., Corona, F., Reales-Calderón, J. A., Sánchez, M. B., & Martínez, J. L. (2016). Multidrug efflux pumps as main players in intrinsic and acquired resistance to antimicrobials. Drug Resistance Updates, 28, 13–27.PubMedCrossRefPubMedCentralGoogle Scholar
  49. Holler, J. G., Christensen, S. B., Slotved, H. C., Rasmussen, H. B., Gúzman, A., Olsen, C. E., Petersen, B., & Mølgaard, P. (2012). Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue Nees. The Journal of Antimicrobial Chemotherapy, 67(5), 1138–1144.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Hou, P. F., Chen, X. Y., Yan, G. F., Wang, Y. P., & Ying, C. M. (2012). Study of the correlation of imipenem resistance with efflux pumps AdeABC, AdeIJK, AdeDE and AbeM in clinical isolates of Acinetobacter baumannii. Chemotherapy, 58(2), 152–158.PubMedCrossRefPubMedCentralGoogle Scholar
  51. Hürlimann, L. M., Corradi, V., Hohl, M., Bloemberg, G. V., Tieleman, D. P., & Seeger, M. A. (2016). The heterodimeric ABC transporter EfrCD mediates multidrug efflux in Enterococcus faecalis. Antimicrobial Agents and Chemotherapy, 60(9), 5400–5411.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Jang, S. (2016). Multidrug efflux pumps in Staphylococcus aureus and their clinical implications. Journal of Microbiology, 54(1), 1–8.CrossRefGoogle Scholar
  53. Kenana, J., Langat, B., Kalicki, C., Inthavong, E., & Kanna, A. (2017). The structure of EmrE and its role in antibiotic resistance. The FASEB Journal, 31(1 Supplement), 777–723.Google Scholar
  54. Kourtesi, C., Ball, A. R., Huang, Y. Y., Jachak, S. M., Vera, D. M. A., Khondkar, P., Gibbons, S., Hamblin, M. R., & Tegos, G. P. (2013). Suppl 1: Microbial efflux systems and inhibitors: Approaches to drug discovery and the challenge of clinical implementation. Open Microbiologica Journal, 7, 34.CrossRefGoogle Scholar
  55. Kovač, J., Šimunović, K., Wu, Z., Klančnik, A., Bucar, F., Zhang, Q., & Možina, S. S. (2015). Antibiotic resistance modulation and modes of action of (−)-α-pinene in campylobacter jejuni. PLoS One, 10(4), e0122871.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Krishnamoorthy, S., Shah, B. P., Lee, H. H., & Martinez, L. R. (2016). Microbicides alter the expression and function of RND-type efflux pump AdeABC in biofilm-associated cells of Acinetobacter baumannii clinical isolates. Antimicrobial Agents and Chemotherapy, 60(1), 57–63.PubMedCrossRefPubMedCentralGoogle Scholar
  57. Kumar, S., Floyd, J. T., He, G., & Varela, M. F. (2013). Bacterial antimicrobial efflux pumps of the MFS and MATE transporter families: A review. Recent Res Dev Antimicrob Agents Chemother, 7, 1–21.Google Scholar
  58. Kumar, R., & Pooja Patial, S. J. (2016). A review on efflux pump inhibitors of gram-positive and gram-negative bacteria from plant sources. International Journal of Current Microbiology and Applied Sciences, 5, 837–855.CrossRefGoogle Scholar
  59. Kuroda, T., & Tsuchiya, T. (2009). Multidrug efflux transporters in the MATE family. Biochimica et Biophysica Acta. Proteins and Proteomics, 1794(5), 763–768.CrossRefGoogle Scholar
  60. Kvist, M., Hancock, V., & Klemm, P. (2008). Inactivation of efflux pumps abolishes bacterial biofilm formation. Applied and Environmental Microbiology, 74(23), 7376–7382.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Lee, M. D., Galazzo, J. L., Staley, A. L., Lee, J. C., Warren, M. S., Fuernkranz, H., Chamberland, S., Lomovskaya, O., & Miller, G. H. (2001). Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco, 56(1–2), 81–85.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Lee, Y. S., Jang, K., & Cha, J. D. (2011). Synergistic antibacterial effect between silibinin and antibiotics in oral bacteria. Journal of Biomedicine & Biotechnology, 2012, 7.Google Scholar
  63. Lekshmi, M., Ammini, P., Adjei, J., Sanford, L. M., Shrestha, U., Kumar, S., & Varela, M. F. (2017). Modulation of antimicrobial efflux pumps of the major facilitator superfamily in Staphylococcus aureus. Review, 4(1), 1–18.Google Scholar
  64. Li, X. Z., & Nikaido, H. (2009). Efflux-mediated drug resistance in bacteria. Drugs, 69(12), 1555–1623.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Lloris-Garcerá, P., Slusky, J. S., Seppälä, S., Prieß, M., Schäfer, L. V., & von Heijne, G. (2013). In vivo Trp scanning of the small multidrug resistance protein EmrE confirms 3D structure models. Journal of Molecular Biology, 425(22), 4642–4651.PubMedCrossRefPubMedCentralGoogle Scholar
  66. Lomovskaya, O., & Bostian, K. A. (2006). Practical applications and feasibility of efflux pump inhibitors in the clinic—A vision for applied use. Biochemical Pharmacology, 71(7), 910–918.PubMedCrossRefPubMedCentralGoogle Scholar
  67. Lomovskaya, O., Warren, M. S., Lee, A., Galazzo, J., Fronko, R., Lee, M., Blais, J., Cho, D., Chamberland, S., Renau, T., & Leger, R. (2001). Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy. Antimicrobial Agents and Chemotherapy, 45(1), 105–116.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lu, S., & Zgurskaya, H. I. (2013). MacA, a periplasmic membrane fusion protein of the macrolide transporter MacAB-TolC, binds lipopolysaccharide core specifically and with high affinity. Journal of Bacteriology, 195(21), 4865–4872.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Mahmood, H. Y., Jamshidi, S., Sutton, J. M., & Rahman, K. M. (2016). Current advances in developing inhibitors of bacterial multidrug efflux pumps. Current Medicinal Chemistry, 23(10), 1062–1081.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Maisuria, V. B., Hosseinidoust, Z., & Tufenkji, N. (2015). Polyphenolic extract from maple syrup potentiates antibiotic susceptibility and reduces biofilm formation of pathogenic bacteria. Applied and Environmental Microbiology, 81(11), 3782–3792.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Marchi, E., Furi, L., Arioli, S., Morrissey, I., Di Lorenzo, V., Mora, D., Giovannetti, L., Oggioni, M. R., & Viti, C. (2015). Novel insight into antimicrobial resistance and sensitivity phenotypes associated to qac and norA genotypes in Staphylococcus aureus. Microbiological Research, 170, 184–194.PubMedCrossRefPubMedCentralGoogle Scholar
  72. Maurya, A., Dwivedi, G. R., Darokar, M. P., & Srivastava, S. K. (2013). Antibacterial and synergy of Clavine alkaloid Lysergol and its derivatives against Nalidixic acid-resistant Escherichia coli. Chemical Biology and Drug Design, 81(4), 484–490.PubMedCrossRefPubMedCentralGoogle Scholar
  73. McCrackin, M. A., Helke, K. L., Galloway, A. M., Poole, A. Z., Salgado, C. D., & Marriott, B. P. (2016). Effect of antimicrobial use in agricultural animals on drug-resistant foodborne campylobacteriosis in humans: A systematic literature review. Critical Reviews in Food Science and Nutrition, 56(13), 2115–2132.PubMedCrossRefPubMedCentralGoogle Scholar
  74. Murakami, S., Nakashima, R., Yamashita, E., & Yamaguchi, A. (2002a). Crystal structure of bacterial multidrug efflux transporter AcrB. Nature, 419(6907), 587.Google Scholar
  75. Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T., & Yamaguchi, A. (2006). Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature, 443(7108), 173.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Nakashima, R., Sakurai, K., Yamasaki, S., Hayashi, K., Nagata, C., Hoshino, K., Onodera, Y., Nishino, K., & Yamaguchi, A. (2013). Structural basis for the inhibition of bacterial multidrug exporters. Nature, 500(7460), 102.PubMedCrossRefPubMedCentralGoogle Scholar
  77. Nguefack, J., Dongmo, J. L., Dakole, C. D., Leth, V., Vismer, H. F., Torp, J., Guemdjom, E. F. N., Mbeffo, M., Tamgue, O., Fotio, D., & Zollo, P. A. (2009). Food preservative potential of essential oils and fractions from Cymbopogon citratus, Ocimum gratissimum and Thymus vulgaris against mycotoxigenic fungi. International Journal of Food Microbiology, 131(2–3), 151–156.PubMedCrossRefPubMedCentralGoogle Scholar
  78. Nguyen, S. T., Kwasny, S. M., Ding, X., Cardinale, S. C., McCarthy, C. T., Kim, H. S., Nikaido, H., Peet, N. P., Williams, J. D., Bowlin, T. L., & Opperman, T. J. (2015). Structure–activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors. Bioorganic & Medicinal Chemistry, 23(9), 2024–2034.CrossRefGoogle Scholar
  79. Nikaido, H. (2009). Multidrug resistance in bacteria. Annual Review of Biochemistry, 78, 119–146.PubMedPubMedCentralCrossRefGoogle Scholar
  80. Nikaido, H., & Pagès, J. M. (2012). Broad-specificity efflux pumps and their role in multidrug resistance of gram-negative bacteria. FEMS Microbiology Reviews, 36(2), 340–363.PubMedCrossRefPubMedCentralGoogle Scholar
  81. Nishino, K., & Yamaguchi, A. (2008). Virulence and drug resistance roles of multidrug efflux pumps in Escherichia coli and Salmonella. Bioscience and Microflora, 27(3), 75–85.CrossRefGoogle Scholar
  82. Opperman, T. J., Kwasny, S. M., Kim, H. S., Nguyen, S. T., Houseweart, C., D’Souza, S., Walker, G. C., Peet, N. P., Nikaido, H., & Bowlin, T. L. (2014). Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrobial Agents and Chemotherapy, 58(2), 722–733.PubMedPubMedCentralCrossRefGoogle Scholar
  83. Pagès, J. M., & Amaral, L. (2009). Mechanisms of drug efflux and strategies to combat them: Challenging the efflux pump of gram-negative bacteria. Biochimica et Biophysica Acta. Proteins and Proteomics, 1794(5), 826–833.CrossRefGoogle Scholar
  84. Pérez, A., Poza, M., Fernández, A., Fernández Mdel, C., Mallo, S., Merino, M., Rumbo-Feal, S., Cabral, M. P., & Bou, G. (2012). Involvement of the AcrAB-TolC efflux pump in the resistance, fitness, and virulence of Enterobacter cloacae. Antimicrobial Agents and Chemotherapy, 56(4), 2084–2090.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Perez, F., Rudin, S. D., Marshall, S. H., Coakley, P., Chen, L., Kreiswirth, B. N., Rather, P. N., Hujer, A. M., Toltzis, P., Van Duin, D., & Paterson, D. L. (2013). OqxAB, a quinolone and olaquindox efflux pump, is widely distributed among multidrug-resistant Klebsiella pneumoniae isolates of human origin. Antimicrobial Agents and Chemotherapy, 57(9), 4602–4603.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Piddock, L. J. (2006). Multidrug-resistance efflux pumps – not just for resistance. Nature Reviews. Microbiology, 4(8), 629.PubMedCrossRefPubMedCentralGoogle Scholar
  87. Piddock, L. J., Garvey, M. I., Rahman, M. M., & Gibbons, S. (2010). Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in gram-negative bacteria. The Journal of Antimicrobial Chemotherapy, 65(6), 1215–1223.PubMedCrossRefPubMedCentralGoogle Scholar
  88. Radchenko, M., Symersky, J., Nie, R., & Lu, M. (2015). Structural basis for the blockade of MATE multidrug efflux pumps. Nature Communications, 6, 7995.PubMedPubMedCentralCrossRefGoogle Scholar
  89. Ramalhete, C., Spengler, G., Martins, A., Martins, M., Viveiros, M., Mulhovo, S., Ferreira, M. J. U., & Amaral, L. (2011a). Inhibition of efflux pumps in methicillin-resistant Staphylococcus aureus and Enterococcus faecalis resistant strains by triterpenoids from Momordica balsamina. International Journal of Antimicrobial Agents, 37(1), 70–74.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Ramalhete, C., Spengler, G., Martins, A., Martins, M., Viveiros, M., Mulhovo, S., Ferreira, M. J., & Amaral, L. (2011b). Inhibition of efflux pumps in methicillin-resistant Staphylococcus aureus and Enterococcus faecalis resistant strains by triterpenoids from Momordica balsamina. International Journal of Antimicrobial Agents, 37(1), 70–74.PubMedCrossRefPubMedCentralGoogle Scholar
  91. Ramalhete, C., Mulhovo, S., Molnar, J., & Ferreira, M. J. (2016). Triterpenoids from Momordica balsamina: Reversal of ABCB1-mediated multidrug resistance. Bioorganic & Medicinal Chemistry, 1;24(21), 5061–5067.CrossRefGoogle Scholar
  92. Ranaweera, I., Shrestha, U., Ranjana, K. C., Kakarla, P., Willmon, T. M., Hernandez, A. J., Mukherjee, M. M., Barr, S. R., & Varela, M. F. (2015). Structural comparison of bacterial multidrug efflux pumps of the major facilitator superfamily. Trends in Cell & Molecular Biology, 10, 131.Google Scholar
  93. Reddy, V. S., Shlykov, M. A., Castillo, R., Sun, E. I., & Saier, M. H. (2012). The major facilitator superfamily (MFS) revisited. The FEBS Journal, 279(11), 2022–2035.PubMedPubMedCentralCrossRefGoogle Scholar
  94. Redgrave, L. S., Sutton, S. B., Webber, M. A., & Piddock, L. J. (2014). Fluoroquinolone resistance: Mechanisms, impact on bacteria, and role in evolutionary success. Trends in Microbiology, 22(8), 438–445.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Schindler, B. D., & Kaatz, G. W. (2016). Multidrug efflux pumps of gram-positive bacteria. Drug Resistance Updates, 27, 1–13.PubMedCrossRefPubMedCentralGoogle Scholar
  96. Schuster, S., Kohler, S., Buck, A., Dambacher, C., König, A., Bohnert, J. A., & Kern, W. V. (2014). Random mutagenesis of the multidrug transporter AcrB from Escherichia coli for identification of putative target residues of efflux pump inhibitors. Antimicrobial Agents and Chemotherapy, 58(11), 6870–6878.PubMedPubMedCentralCrossRefGoogle Scholar
  97. Sennhauser, G., Bukowska, M. A., Briand, C., & Grütter, M. G. (2009). Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. Journal of Molecular Biology, 389(1), 134–145.PubMedCrossRefPubMedCentralGoogle Scholar
  98. Shiu, W. K., Malkinson, J. P., Rahman, M. M., Curry, J., Stapleton, P., Gunaratnam, M., Neidle, S., Mushtaq, S., Warner, M., Livermore, D. M., & Evangelopoulos, D. (2013). A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus. International Journal of Antimicrobial Agents, 42(6), 513–518.PubMedCrossRefPubMedCentralGoogle Scholar
  99. Singh, K. V., Malathum, K., & Murray, B. E. (2001). Disruption of an Enterococcus faecium species-specific gene, a homologue of acquired macrolide resistance genes of staphylococci, is associated with an increase in macrolide susceptibility. Antimicrobial Agents and Chemotherapy, 45(1), 263–266.PubMedPubMedCentralCrossRefGoogle Scholar
  100. Singh, M., Yau, Y. C., Wang, S., Waters, V., & Kumar, A. (2017). MexXY efflux pump overexpression and aminoglycoside resistance in cystic fibrosis isolates of Pseudomonas aeruginosa from chronic infections. Canadian Journal of Microbiology, 63(12), 929–938.PubMedCrossRefPubMedCentralGoogle Scholar
  101. Sjuts, H., Vargiu, A. V., Kwasny, S. M., Nguyen, S. T., Kim, H. S., Ding, X., Ornik, A. R., Ruggerone, P., Bowlin, T. L., Nikaido, H., & Pos, K. M. (2016). Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives. Proceedings of the National Academy of Sciences of the United States of America, 29;113(13), 3509–3514.CrossRefGoogle Scholar
  102. Smith, E. C., Williamson, E. M., Wareham, N., Kaatz, G. W., & Gibbons, S. (2007). Antibacterials and modulators of bacterial resistance from the immature cones of Chamaecyparis lawsoniana. Phytochemistry, 68(2), 210–217.PubMedCrossRefPubMedCentralGoogle Scholar
  103. Stermitz, F. R., Tawara-Matsuda, J., Lorenz, P., Mueller, P., Zenewicz, L., & Lewis, K. (2000). 5′-Methoxyhydnocarpin-D and Pheophorbide A: Berberis species components that Potentiate Berberine growth inhibition of resistant Staphylococcus aureus. Journal of natural products, 63(8), 1146–1149.PubMedCrossRefPubMedCentralGoogle Scholar
  104. Su, C. C., Yin, L., Kumar, N., Dai, L., Radhakrishnan, A., Bolla, J. R., Lei, H. T., Chou, T. H., Delmar, J. A., Rajashankar, K. R., & Zhang, Q. (2017). Structures and transport dynamics of a Campylobacter jejuni multidrug efflux pump. Nature Communications, 8(1), 171.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Sun, J., Deng, Z., & Yan, A. (2014). Bacterial multidrug efflux pumps: Mechanisms, physiology and pharmacological exploitations. Biochemical and Biophysical Research Communications, 453(2), 254–267.Google Scholar
  106. Tanabe, M., Szakonyi, G., Brown, K. A., Henderson, P. J., Nield, J., & Byrne, B. (2009). The multidrug resistance efflux complex, EmrAB from Escherichia coli forms a dimer in vitro. Biochemical and Biophysical Research Communications, 380(2), 338–342.PubMedCrossRefPubMedCentralGoogle Scholar
  107. Tegos, G., Masago, K., Aziz, F., Higginbotham, A., Stermitz, F. R., & Hamblin, M. R. (2008). Inhibitors of bacterial multidrug efflux pumps potentiate antimicrobial photoinactivation. Antimicrobial Agents and Chemotherapy, 52(9), 3202–3209.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Tegos, G. P., Haynes, M., Jacob Strouse, J., Khan, M. M. T., Bologa, C. G., Oprea, T. I., & Sklar, L. A. (2011). Microbial efflux pump inhibition: Tactics and strategies. Current Pharmaceutical Design, 17(13), 1291–1302.PubMedPubMedCentralCrossRefGoogle Scholar
  109. Tocci, N., Iannelli, F., Bidossi, A., Ciusa, M. L., Decorosi, F., Viti, C., Pozzi, G., Ricci, S., & Oggioni, M. R. (2013). Functional analysis of pneumococcal drug efflux pumps associates the MATE DinF transporter with quinolone susceptibility. Antimicrobial Agents and Chemotherapy, 57(1), 248–253.PubMedPubMedCentralCrossRefGoogle Scholar
  110. van der Putten, B. C., Pasquini, G., Remondini, D., Janes, V. A., Matamoros, S., & Schultsz, C. (2018 Jan). Quantifying the contribution of four resistance mechanisms to ciprofloxacin minimum inhibitory concentration in Escherichia coli: A systematic review. bioRxiv, 1, 372086.Google Scholar
  111. Vargiu, A. V., Ruggerone, P., Opperman, T. J., Nguyen, S. T., & Nikaido, H. (2014). Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob Agents Chemother, 58(10), 6224–6234.Google Scholar
  112. Vargiu, A. V., & Nikaido, H. (2012). Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Nat Acad Sci, 109(50), 20637–20642.PubMedCrossRefPubMedCentralGoogle Scholar
  113. Venter, H., Mowla, R., Ohene-Agyei, T., & Ma, S. (2015). RND-type drug efflux pumps from gram-negative bacteria: Molecular mechanism and inhibition. Frontiers in Microbiology, 6, 377.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Wassenaar, T., Ussery, D., Nielsen, L., & Ingmer, H. (2015). Review and phylogenetic analysis of qac genes that reduce susceptibility to quaternary ammonium compounds in Staphylococcus species. European Journal of Microbiology & Immunology, 1;5(1), 44–61.CrossRefGoogle Scholar
  115. Wendlandt, S., Kadlec, K., Feßler, A. T., & Schwarz, S. (2015). Identification of ABC transporter genes conferring combined pleuromutilin–lincosamide–streptogramin A resistance in bovine methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci. Veterinary Microbiology, 177(3–4), 353–358.PubMedCrossRefPubMedCentralGoogle Scholar
  116. Wilkens, S. (2015). Structure and mechanism of ABC transporters. F1000Prime Rep, 7, 14.PubMedPubMedCentralCrossRefGoogle Scholar
  117. Wink, M. (2012). Secondary metabolites from plants inhibiting ABC transporters and reversing resistance of cancer cells and microbes to cytotoxic and antimicrobial agents. Frontiers in Microbiology, 23(3), 130.Google Scholar
  118. World Health Organization. (2014). Antimicrobial resistance: Global report on surveillance. Geneva: World Health Organization.Google Scholar
  119. Yamaguchi, A., Nakashima, R., & Sakurai, K. (2015). Structural basis of RND-type multidrug exporters. Frontiers in Microbiology, 6, 327.PubMedPubMedCentralCrossRefGoogle Scholar
  120. Yao, H., Shen, Z., Wang, Y., Deng, F., Liu, D., Naren, G., Dai, L., Su, C. C., Wang, B., Wang, S., & Wu, C. (2016). Emergence of a potent multidrug efflux pump variant that enhances Campylobacter resistance to multiple antibiotics. MBio, 7(5), e01543–e01516.PubMedPubMedCentralCrossRefGoogle Scholar
  121. Yin, C. C., Aldema-Ramos, M. L., Borges-Walmsley, M. I., Taylor, R. W., Walmsley, A. R., Levy, S. B., & Bullough, P. A. (2000). The quarternary molecular architecture of TetA, a secondary tetracycline transporter from Escherichia coli. Journal Molecular Microbiology, 38(3), 482–492.PubMedCrossRefPubMedCentralGoogle Scholar
  122. Yoshida, K. I., Nakayama, K., Ohtsuka, M., Kuru, N., Yokomizo, Y., Sakamoto, A., Takemura, M., Hoshino, K., Kanda, H., Nitanai, H., & Namba, K. (2007). MexAB-OprM specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 7: Highly soluble and in vivo active quaternary ammonium analogue D13-9001, a potential preclinical candidate. Bioorg Med Chem, 15(22), 7087–7097.Google Scholar
  123. Yu, J. L., Grinius, L., Hooper, D. C. (2002, March 1). NorA functions as a multidrug efflux p rotein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes. Journal of Bacteriology, 184(5), 1370–1377.PubMedPubMedCentralCrossRefGoogle Scholar
  124. Zhang, C. Z., Chen, P. X., Yang, L., Li, W., Chang, M. X., & Jiang, H. X. (2018). Coordinated expression of acrAB-tolC and eight other functional efflux pumps through activating ramA and marA in Salmonella enterica serovar Typhimurium. Microbial Drug Resistance, 24(2), 120–125.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Samreen
    • 1
  • Iqbal Ahmad
    • 1
  • Faizan Abul Qais
    • 1
  • Meenu Maheshwari
    • 1
  • Kendra P. Rumbaugh
    • 2
  1. 1.Department of Agricultural Microbiology, Faculty of Agricultural SciencesAligarh Muslim UniversityAligarhIndia
  2. 2.School of MedicineTexas Tech University Health Sciences CenterLubbockUSA

Personalised recommendations