Skip to main content
SpringerLink
Log in

Antimicrobial Drug Efflux Pump Inhibitors

  • Chapter
  • First Online:
Efflux-Mediated Antimicrobial Resistance in Bacteria

  • 2155 Accesses

Abstract

Bacterial multidrug resistance is on the rise, and bacterial efflux pumps make a major contributor to this development. Efflux pump inhibitors (EPIs) may be a solution to this problem, since they can reverse resistance to clinically administered antimicrobial agents. Multiple EPIs with activity against Gram-positive and Gram-negative bacteria have been described over the past decades. However, none of the synthetic EPIs have currently reached a stage of clinical applicability. Investigators have evaluated certain drugs already in clinical use for their ability to potentiate the activity of antimicrobials via inhibition of drug efflux pumps. Most of the compounds reported to date do not reach clinical concentrations for EPI activity at the in vivo target site, with a notable exception, i.e., thioridazine shown to potentiate the killing of Mycobacterium tuberculosis in human macrophages. Our understanding of the molecular mechanisms for efflux pump inhibition has been considerably advanced, mainly because of the availability of crystal structures of multidrug transporters, including those in complex with substrates or EPIs (in particular with the AcrAB-TolC efflux system of Escherichia coli). Crystallographic data as well as results from mutagenesis and computational chemistry studies have laid the foundation for rational EPI design.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ruppe E, Woerther PL, Barbier F (2015) Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensiv Care 5:61. doi:10.1186/s13613-015-0061-0

    Google Scholar 

  2. 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

    Article  CAS  PubMed  Google Scholar 

  3. Elemam A, Rahimian J, Doymaz M (2010) In vitro evaluation of antibiotic synergy for polymyxin B-resistant carbapenemase-producing Klebsiella pneumoniae. J Clin Microbiol 48:3558–3562. doi:10.1128/JCM.01106-10

    Google Scholar 

  4. Stein C, Makarewicz O, Bohnert JA, Pfeifer Y, Kesselmeier M, Hagel S, Pletz MW (2015) Three dimensional checkerboard synergy analysis of colistin, meropenem, tigecycline against multidrug-resistant clinical Klebsiella pneumonia isolates. PLoS One 10:e0126479. doi:10.1371/journal.pone.0126479

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Ordooei Javan A, Shokouhi S, Sahraei Z (2015) A review on colistin nephrotoxicity. Eur J Clin Pharmacol 71:801–810. doi:10.1007/s00228-015-1865-4

    Article  CAS  PubMed  Google Scholar 

  6. Mingeot-Leclercq MP, Tulkens PM, Denamur S, Vaara T, Vaara M (2012) Novel polymyxin derivatives are less cytotoxic than polymyxin B to renal proximal tubular cells. Peptides 35:248–252. doi:10.1016/j.peptides.2012.03.033

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. Laudy AE, Osinska P, Namyslowska A, Zajac O, Tyski S (2015) Modification of the susceptibility of Gram-negative rods producing ESBLs to β-lactams by the efflux phenomenon. PLoS One 10:e0119997. doi:10.1371/journal.pone.0119997

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Bohnert JA, Kern WV (2005) Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother 49:849–852. doi:10.1128/AAC.49.2.849-852.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lomovskaya O, Watkins W (2001) Inhibition of efflux pumps as a novel approach to combat drug resistance in bacteria. J Mol Microbiol Biotechnol 3:225–236

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bohnert JA, Schuster S, Szymaniak-Vits M, Kern WV (2011) Determination of real-time efflux phenotypes in Escherichia coli AcrB binding pocket phenylalanine mutants using a 1,2′-dinaphthylamine efflux assay. PLoS One 6:e21196. doi:10.1371/journal.pone.0021196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Iyer R, Ferrari A, Rijnbrand R, Erwin AL (2015) A fluorescent microplate assay quantifies bacterial efflux and demonstrates two distinct compound binding sites in AcrB. Antimicrob Agents Chemother 59:2388–2397. doi:10.1128/AAC.05112-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Neyfakh AA, Bidnenko VE, Chen LB (1991) Efflux-mediated multidrug resistance in Bacillus subtilis: similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci U S A 88:4781–4785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rodrigues L, Viveiros M, Ainsa JA (2015) Measuring efflux and permeability in mycobacteria. Methods Mol Biol 1285:227–239. doi:10.1007/978-1-4939-2450-9_13

    Article  CAS  PubMed  Google Scholar 

  19. Viveiros M, Martins A, Paixao L, Rodrigues L, Martins M, Couto I, Fahnrich E, Kern WV et al (2008) Demonstration of intrinsic efflux activity of Escherichia coli K-12 AG100 by an automated ethidium bromide method. Int J Antimicrob Agents 31:458–462. doi:10.1016/j.ijantimicag.2007.12.015

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Smirk FH, Doyle AE, McQueen EG (1954) Control of blood-pressure by combined action of reserpine and pentapyrrolidinium. Lancet 264:159–162. doi:10.1016/S0140-6736(54)90137-3

    Article  Google Scholar 

  23. Inaba M, Fujikura R, Tsukagoshi S, Sakurai Y (1981) Restored in vitro sensitivity of adriamycin- and vincristine-resistant P388 leukemia with reserpine. Biochem Pharmacol 30:2191–2194. doi:10.1016/0006-2952(81)90246-X

    Google Scholar 

  24. Tsuruo T, Iida H, Tsukagoshi S, Sakurai Y (1981) Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res 41:1967–1972

    Google Scholar 

  25. Neyfakh AA (1988) Use of fluorescent dyes as molecular probes for the study of multidrug resistance. Exp Cell Res 174:168–176. doi:10.1016/0014-4827(88)90152-8

    Article  CAS  PubMed  Google Scholar 

  26. Akiyama S, Cornwell MM, Kuwano M, Pastan I, Gottesman MM (1988) Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog. Mol Pharmacol 33:144–147

    CAS  PubMed  Google Scholar 

  27. Ahmed M, Borsch CM, Neyfakh AA, Schuldiner S (1993) Mutants of the Bacillus subtilis multidrug transporter Bmr with altered sensitivity to the antihypertensive alkaloid reserpine. J Biol Chem 268:11086–11089

    CAS  PubMed  Google Scholar 

  28. Klyachko KA, Schuldiner S, Neyfakh AA (1997) Mutations affecting substrate specificity of the Bacillus subtilis multidrug transporter Bmr. J Bacteriol 179:2189–2193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klyachko KA, Neyfakh AA (1998) Paradoxical enhancement of the activity of a bacterial multidrug transporter caused by substitutions of a conserved residue. J Bacteriol 180:2817–2821

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zheleznova EE, Markham PN, Neyfakh AA, Brennan RG (1999) Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter. Cell 96:353–362. doi:10.1016/S0092-8674(00)80548-6

    Article  CAS  PubMed  Google Scholar 

  31. Neyfakh AA, Borsch CM, Kaatz GW (1993) Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrob Agents Chemother 37:128–129. doi:10.1128/AAC.37.1.128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mitchell BA, Paulsen IT, Brown MH, Skurray RA (1999) Bioenergetics of the staphylococcal multidrug export protein QacA. Identification of distinct binding sites for monovalent and divalent cations. J Biol Chem 274:3541–3548. doi:10.1074/jbc.274.6.3541

    Article  CAS  PubMed  Google Scholar 

  33. Patel D, Kosmidis C, Seo SM, Kaatz GW (2010) Ethidium bromide MIC screening for enhanced efflux pump gene expression or efflux activity in Staphylococcus aureus. Antimicrob Agents Chemother 54:5070–5073. doi:10.1128/AAC.01058-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brenwald NP, Gill MJ, Wise R (1997) The effect of reserpine, an inhibitor of multi-drug efflux pumps, on the in-vitro susceptibilities of fluoroquinolone-resistant strains of Streptococcus pneumoniae to norfloxacin. J Antimicrob Chemother 40:458–460. doi:10.1093/jac/40.3.458

    Google Scholar 

  35. Jonas BM, Murray BE, Weinstock GM (2001) Characterization of EmeA, a NorA homolog and multidrug resistance efflux pump, in Enterococcus faecalis. Antimicrob Agents Chemother 45:3574–3579. doi:10.1128/AAC.45.12.3574-3579.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Godreuil S, Galimand M, Gerbaud G, Jacquet C, Courvalin P (2003) Efflux pump Lde is associated with fluoroquinolone resistance in Listeria monocytogenes. Antimicrob Agents Chemother 47:704–708. doi:10.1128/AAC.47.2.704-708.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Piddock LJ, Williams KJ, Ricci V (2000) Accumulation of rifampicin by Mycobacterium aurum, Mycobacterium smegmatis and Mycobacterium tuberculosis. J Antimicrob Chemother 45:159–165. doi:10.1093/jac/45.2.159

    Article  CAS  PubMed  Google Scholar 

  38. Silva PE, Bigi F, de la Paz Santangelo M, Romano MI, Martin C, Cataldi A, Ainsa JA (2001) Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother 45:800–804. doi:10.1128/AAC.45.3.800-804.2001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Viveiros M, Portugal I, Bettencourt R, Victor TC, Jordaan AM, Leandro C, Ordway D, Amaral L (2002) Isoniazid-induced transient high-level resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 46:2804–2810. doi:10.1128/AAC.46.9.2804-2810.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ramón-García S, Martin C, Aínsa JA, De Rossi E (2006) Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum. J Antimicrob Chemother 57:252–259. doi:10.1093/jac/dki436

    Article  PubMed  CAS  Google Scholar 

  41. Choudhuri BS, Sen S, Chakrabarti P (1999) Isoniazid accumulation in Mycobacterium smegmatis is modulated by proton motive force-driven and ATP-dependent extrusion systems. Biochem Biophys Res Commun 256:682–684. doi:10.1006/bbrc.1999.0357

    Article  CAS  PubMed  Google Scholar 

  42. Millward MJ, Cantwell BM, Munro NC, Robinson A, Corris PA, Harris AL (1993) Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study. Br J Cancer 67:1031–1035. doi:10.1038/bjc.1993.189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schwartz JB, Todd E, Abernethy DR, Mitchell JR (1986) Steady state verapamil tissue distribution in the dog: differing tissue accumulation. Pharmacology 32:307–312. doi:10.1159/000138185

    Article  CAS  PubMed  Google Scholar 

  44. Gupta S, Tyagi S, Bishai WR (2015) Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother 59:673–676. doi:10.1128/AAC.04019-14

    Article  PubMed  CAS  Google Scholar 

  45. Gupta S, Cohen KA, Winglee K, Maiga M, Diarra B, Bishai WR (2014) Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob Agents Chemother 58:574–576. doi:10.1128/AAC.01462-13

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Li G, Zhang J, Guo Q, Jiang Y, Wei J, Zhao LL, Zhao X, Lu J et al (2015) Efflux pump gene expression in multidrug-resistant Mycobacterium tuberculosis clinical isolates. PLoS One 10:e0119013. doi:10.1371/journal.pone.0119013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Pasca MR, Guglierame P, Arcesi F, Bellinzoni M, De Rossi E, Riccardi G (2004) Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob Agents Chemother 48:3175–3178. doi:10.1128/AAC.48.8.3175-3178.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mullin S, Mani N, Grossman TH (2004) Inhibition of antibiotic efflux in bacteria by the novel multidrug resistance inhibitors biricodar (VX-710) and timcodar (VX-853). Antimicrob Agents Chemother 48:4171–4176. doi:10.1128/AAC.48.11.4171-4176.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Grossman TH, Shoen CM, Jones SM, Jones PL, Cynamon MH, Locher CP (2015) The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents. Antimicrob Agents Chemother 59:1534–1541. doi:10.1128/AAC.04271-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gibbons S, Oluwatuyi M, Kaatz GW (2003) A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus. J Antimicrob Chemother 51:13–17. doi:10.1093/jac/dkg044

    Article  CAS  PubMed  Google Scholar 

  51. Leitner I, Nemeth J, Feurstein T, Abrahim A, Matzneller P, Lagler H, Erker T, Langer O et al (2011) The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration. J Antimicrob Chemother 66:834–839. doi:10.1093/jac/dkq526

    Article  CAS  PubMed  Google Scholar 

  52. Abraham J, Edgerly M, Wilson R, Chen C, Rutt A, Bakke S, Robey R, Dwyer A et al (2009) A phase I study of the P-glycoprotein antagonist tariquidar in combination with vinorelbine. Clin Cancer Res 15:3574–3582. doi:10.1158/1078-0432.CCR-08-0938

    Article  CAS  PubMed  Google Scholar 

  53. Palmeira A, Sousa E, Vasconcelos MH, Pinto MM (2012) Three decades of P-gp inhibitors: skimming through several generations and scaffolds. Curr Med Chem 19:1946–2025. doi:10.2174/092986712800167392

    Article  CAS  PubMed  Google Scholar 

  54. Aeschlimann JR, Dresser LD, Kaatz GW, Rybak MJ (1999) Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus. Antimicrob Agents Chemother 43:335–340

    Google Scholar 

  55. Sabatini S, Gosetto F, Serritella S, Manfroni G, Tabarrini O, Iraci N, Brincat JP, Carosati E et al (2012) Pyrazolo[4,3-c][1,2]benzothiazines 5,5-dioxide: a promising new class of Staphylococcus aureus NorA efflux pump inhibitors. J Med Chem 55:3568–3572. doi:10.1021/jm201446h

    Article  CAS  PubMed  Google Scholar 

  56. Winkelman NW Jr (1954) Chlorpromazine in the treatment of neuropsychiatric disorders. JAMA 155:18–21. doi:10.1001/jama.1954.03690190024007

    Article  CAS  Google Scholar 

  57. Kristiansen JE, Mortensen I (1981) Stereo-isomeric dissociation of the antibacterial and the neuroleptic effect of clopenthixol. Acta Pathol Microbiol Scand B 89:437–438

    CAS  PubMed  Google Scholar 

  58. Kristiansen JE, Mortensen I (1987) Antibacterial effect of four phenothiazines. Pharmacol Toxicol 60:100–103. doi:10.1111/j.1600-0773.1987.tb01504.x

    Article  CAS  PubMed  Google Scholar 

  59. Amaral L, Kristiansen J, Lorian V (1992) Synergic effect of chlorpromazine on the activity of some antibiotics. J Antimicrob Chemother 30:556–558. doi:10.1093/jac/30.4.556

    Article  CAS  PubMed  Google Scholar 

  60. Amaral L, Kristiansen JE (2000) Phenothiazines: an alternative to conventional therapy for the initial management of suspected multidrug resistant tuberculosis. A call for studies. Int J Antimicrob Agents 14:173–176. doi:10.1016/S0924-8579(99)00153-3

    Article  CAS  PubMed  Google Scholar 

  61. Amaral L, Kristiansen JE, Viveiros M, Atouguia J (2001) Activity of phenothiazines against antibiotic-resistant Mycobacterium tuberculosis: a review supporting further studies that may elucidate the potential use of thioridazine as anti-tuberculosis therapy. J Antimicrob Chemother 47:505–511. doi:10.1093/jac/47.5.505

    Article  CAS  PubMed  Google Scholar 

  62. Ordway D, Viveiros M, Leandro C, Arroz MJ, Amaral L (2002) Intracellular activity of clinical concentrations of phenothiazines including thioridazine against phagocytosed Staphylococcus aureus. Int J Antimicrob Agents 20:34–43. doi:10.1016/S0924-8579(02)00110-3

    Article  CAS  PubMed  Google Scholar 

  63. Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE (2003) Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother 47:719–726. doi:10.1128/AAC.47.2.719-726.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Couto I, Costa SS, Viveiros M, Martins M, Amaral L (2008) Efflux-mediated response of Staphylococcus aureus exposed to ethidium bromide. J Antimicrob Chemother 62:504–513. doi:10.1093/jac/dkn217

    Article  CAS  PubMed  Google Scholar 

  65. Sabatini S, Kaatz GW, Rossolini GM, Brandini D, Fravolini A (2008) From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. J Med Chem 51:4321–4330. doi:10.1021/jm701623q

    Article  CAS  PubMed  Google Scholar 

  66. Rodrigues L, Wagner D, Viveiros M, Sampaio D, Couto I, Vavra M, Kern WV, Amaral L (2008) Thioridazine and chlorpromazine inhibition of ethidium bromide efflux in Mycobacterium avium and Mycobacterium smegmatis. J Antimicrob Chemother 61:1076–1082. doi:10.1093/jac/dkn070

    Article  CAS  PubMed  Google Scholar 

  67. Coelho T, Machado D, Couto I, Maschmann R, Ramos D, von Groll A, Rossetti ML, Silva PA et al (2015) Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil. Front Microbiol 6:330. doi:10.3389/fmicb.2015.00330

    Article  PubMed  PubMed Central  Google Scholar 

  68. Abbate E, Vescovo M, Natiello M, Cufre M, Garcia A, Gonzalez Montaner P, Ambroggi M, Ritacco V et al (2012) Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother 67:473–477. doi:10.1093/jac/dkr500

    Article  CAS  PubMed  Google Scholar 

  69. Udwadia ZF, Sen T, Pinto LM (2011) Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB. Recent Pat Antiinfect Drug Discov 6:88–91. doi:10.2174/157489111796064614

    Article  CAS  PubMed  Google Scholar 

  70. van Soolingen D, Hernandez-Pando R, Orozco H, Aguilar D, Magis-Escurra C, Amaral L, van Ingen J, Boeree MJ (2010) The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis. PLoS One 5:e12640. doi:10.1371/journal.pone.0012640

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Bettencourt MV, Bosne-David S, Amaral L (2000) Comparative in vitro activity of phenothiazines against multidrug-resistant Mycobacterium tuberculosis. Int J Antimicrob Agents 16:69–71. doi:10.1016/S0924-8579(00)00199-0

    Google Scholar 

  72. Crowle AJ, Douvas GS, May MH (1992) Chlorpromazine: a drug potentially useful for treating mycobacterial infections. Chemotherapy 38:410–419. doi:10.1159/000239036

    Article  CAS  PubMed  Google Scholar 

  73. Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, Kristiansen JE, Molnar J et al (2003) Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 47:917–922. doi:10.1128/AAC.47.3.917-922.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Amaral L, Martins M, Viveiros M (2007) Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J Antimicrob Chemother 59:1237–1246. doi:10.1093/jac/dkl500

    Article  CAS  PubMed  Google Scholar 

  75. Kaatz GW, Moudgal VV, Seo SM, Hansen JB, Kristiansen JE (2003) Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. Int J Antimicrob Agents 22:254–261. doi:10.1016/S0924-8579(03)00220-6

    Article  CAS  PubMed  Google Scholar 

  76. German N, Kaatz GW, Kerns RJ (2008) Synthesis and evaluation of PSSRI-based inhibitors of Staphylococcus aureus multidrug efflux pumps. Bioorg Med Chem Lett 18:1368–1373. doi:10.1016/j.bmcl.2008.01.014

    Article  CAS  PubMed  Google Scholar 

  77. Holler JG, Christensen SB, Slotved HC, Rasmussen HB, Guzman A, Olsen CE, Petersen B, Molgaard P (2012) Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue Nees. J Antimicrob Chemother 67:1138–1144. doi:10.1093/jac/dks005

    Article  CAS  PubMed  Google Scholar 

  78. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K (2000) Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci U S A 97:1433–1437. doi:10.1073/pnas.030540597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Guz NR, Stermitz FR, Johnson JB, Beeson TD, Willen S, Hsiang J, Lewis K (2001) Flavonolignan and flavone inhibitors of a Staphylococcus aureus multidrug resistance pump: structure-activity relationships. J Med Chem 44:261–268. doi:10.1021/jm0004190

    Article  CAS  PubMed  Google Scholar 

  80. Stermitz FR, 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. J Nat Prod 63:1146–1149. doi:10.1021/np990639k

    Article  CAS  PubMed  Google Scholar 

  81. Musumeci R, Speciale A, Costanzo R, Annino A, Ragusa S, Rapisarda A, Pappalardo MS, Iauk L (2003) Berberis aetnensis C. Presl. extracts: antimicrobial properties and interaction with ciprofloxacin. Int J Antimicrob Agents 22:48–53. doi:10.1016/S0924-8579(03)00085-2

    Article  CAS  PubMed  Google Scholar 

  82. Pereda-Miranda R, Kaatz GW, Gibbons S (2006) Polyacylated oligosaccharides from medicinal Mexican morning glory species as antibacterials and inhibitors of multidrug resistance in Staphylococcus aureus. J Nat Prod 69:406–409. doi:10.1021/np050227d

    Article  CAS  PubMed  Google Scholar 

  83. Fiamegos YC, Kastritis PL, Exarchou V, Han H, Bonvin AM, Vervoort J, Lewis K, Hamblin MR et al (2011) Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against Gram-positive pathogenic bacteria. PLoS One 6:e18127. doi:10.1371/journal.pone.0018127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mirza ZM, Kumar A, Kalia NP, Zargar A, Khan IA (2011) Piperine as an inhibitor of the MdeA efflux pump of Staphylococcus aureus. J Med Microbiol 60:1472–1478. doi:10.1099/jmm.0.033167-0

    Article  CAS  PubMed  Google Scholar 

  85. Jin J, Zhang J, Guo N, Feng H, Li L, Liang J, Sun K, Wu X et al (2011) The plant alkaloid piperine as a potential inhibitor of ethidium bromide efflux in Mycobacterium smegmatis. J Med Microbiol 60:223–229. doi:10.1099/jmm.0.025734-0

    Article  CAS  PubMed  Google Scholar 

  86. Sharma S, Kumar M, Sharma S, Nargotra A, Koul S, Khan IA (2010) Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother 65:1694–1701. doi:10.1093/jac/dkq186

    Article  CAS  PubMed  Google Scholar 

  87. Sharma S, Kalia NP, Suden P, Chauhan PS, Kumar M, Ram AB, Khajuria A, Bani S et al (2014) Protective efficacy of piperine against Mycobacterium tuberculosis. Tuberculosis 94:389–396. doi:10.1016/j.tube.2014.04.007

    Article  CAS  PubMed  Google Scholar 

  88. Jin J, Zhang JY, Guo N, Sheng H, Li L, Liang JC, Wang XL, Li Y et al (2010) Farnesol, a potential efflux pump inhibitor in Mycobacterium smegmatis. Molecules 15:7750–7762. doi:10.3390/molecules15117750

    Article  CAS  PubMed  Google Scholar 

  89. Morel C, Stermitz FR, Tegos G, Lewis K (2003) Isoflavones as potentiators of antibacterial activity. J Agric Food Chem 51:5677–5679. doi:10.1021/jf0302714

    Article  CAS  PubMed  Google Scholar 

  90. Gibbons S, Moser E, Kaatz GW (2004) Catechin gallates inhibit multidrug resistance (MDR) in Staphylococcus aureus. Planta Med 70:1240–1242. doi:10.1055/s-2004-835860

    Article  CAS  PubMed  Google Scholar 

  91. Maia GL, Falcao-Silva Vdos S, Aquino PG, de Araujo-Junior JX, Tavares JF, da Silva MS, Rodrigues LC, de Siqueira-Junior JP et al (2011) Flavonoids from Praxelis clematidea R.M. King and Robinson modulate bacterial drug resistance. Molecules 16:4828–4835. doi:10.3390/molecules16064828

    Article  CAS  PubMed  Google Scholar 

  92. Falcão-Silva VS, Silva DA, Souza MD, Siqueira-Junior JP (2009) Modulation of drug resistance in Staphylococcus aureus by a kaempferol glycoside from Herissantia tiubae (Malvaceae). Phytother Res 23:1367–1370. doi:10.1002/ptr.2695

    Google Scholar 

  93. 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

    Article  CAS  PubMed  Google Scholar 

  94. Oluwatuyi M, Kaatz GW, Gibbons S (2004) Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry 65:3249–3254. doi:10.1016/j.phytochem.2004.10.009

    Article  CAS  PubMed  Google Scholar 

  95. German N, Wei P, Kaatz GW, Kerns RJ (2008) Synthesis and evaluation of fluoroquinolone derivatives as substrate-based inhibitors of bacterial efflux pumps. Eur J Med Chem 43:2453–2463. doi:10.1016/j.ejmech.2008.01.042

    Article  CAS  PubMed  Google Scholar 

  96. Pieroni M, Dimovska M, Brincat JP, Sabatini S, Carosati E, Massari S, Kaatz GW, Fravolini A (2010) From 6-aminoquinoline antibacterials to 6-amino-7-thiopyranopyridinylquinolone ethyl esters as inhibitors of Staphylococcus aureus multidrug efflux pumps. J Med Chem 53:4466–4480. doi:10.1021/jm1003304

    Article  CAS  PubMed  Google Scholar 

  97. Sabatini S, Gosetto F, Manfroni G, Tabarrini O, Kaatz GW, Patel D, Cecchetti V (2011) Evolution from a natural flavones nucleus to obtain 2-(4-propoxyphenyl)quinoline derivatives as potent inhibitors of the S. aureus NorA efflux pump. J Med Chem 54:5722–5736. doi:10.1021/jm200370y

    Article  CAS  PubMed  Google Scholar 

  98. Sabatini S, Gosetto F, Iraci N, Barreca ML, Massari S, Sancineto L, Manfroni G, Tabarrini O et al (2013) Re-evolution of the 2-phenylquinolines: ligand-based design, synthesis, and biological evaluation of a potent new class of Staphylococcus aureus NorA efflux pump inhibitors to combat antimicrobial resistance. J Med Chem 56:4975–4989. doi:10.1021/jm400262a

    Article  CAS  PubMed  Google Scholar 

  99. Markham PN, Westhaus E, Klyachko K, Johnson ME, Neyfakh AA (1999) Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Antimicrob Agents Chemother 43:2404–2408

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Samosorn S, Bremner JB, Ball A, Lewis K (2006) Synthesis of functionalized 2-aryl-5-nitro-1H-indoles and their activity as bacterial NorA efflux pump inhibitors. Bioorg Med Chem 14:857–865. doi:10.1016/j.bmc.2005.09.019

    Article  CAS  PubMed  Google Scholar 

  101. Kumar A, Khan IA, Koul S, Koul JL, Taneja SC, Ali I, Ali F, Sharma S et al (2008) Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus. J Antimicrob Chemother 61:1270–1276. doi:10.1093/jac/dkn088

    Article  CAS  PubMed  Google Scholar 

  102. Yin Y, He X, Szewczyk P, Nguyen T, Chang G (2006) Structure of the multidrug transporter EmrD from Escherichia coli. Science 312:741–744. doi:10.1126/science.1125629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Heng J, Zhao Y, Liu M, Liu Y, Fan J, Wang X, Zhao Y, Zhang XC (2015) Substrate-bound structure of the E. coli multidrug resistance transporter MdfA. Cell Res 25:1060–1073. doi:10.1038/cr.2015.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Neyfakh AA (2001) The ostensible paradox of multidrug recognition. J Mol Microbiol Biotechnol 3:151–154

    CAS  PubMed  Google Scholar 

  105. Neyfakh AA (2002) Mystery of multidrug transporters: the answer can be simple. Mol Microbiol 44:1123–1130. doi:10.1046/j.1365-2958.2002.02965.x

    Article  CAS  PubMed  Google Scholar 

  106. Nikaido H, Vaara M (1985) Molecular basis of bacterial outer membrane permeability. Microbiol Rev 49:1–32

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Li X-Z, Plésiat P, Nikaido H (2015) The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev 28:337–418. doi:10.1128/CMR.00117-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Li X-Z, Nikaido H (2009) Efflux-mediated drug resistance in bacteria: an update. Drugs 69:1555–1623. doi:10.2165/11317030-000000000-00000

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Renau TE, Leger R, Flamme EM, Sangalang J, She MW, Yen R, Gannon CL, Griffith D et al (1999) Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin. J Med Chem 42:4928–4931. doi:10.1021/jm9904598

    Article  CAS  PubMed  Google Scholar 

  112. Lamers RP, Cavallari JF, Burrows LL (2013) The efflux inhibitor phenylalanine-arginine β-naphthylamide (PAbN) permeabilizes the outer membrane of Gram-negative bacteria. PLoS One 8:e60666. doi:10.1371/journal.pone.0060666

    Google Scholar 

  113. Yu EW, Aires JR, McDermott G, Nikaido H (2005) A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study. J Bacteriol 187:6804–6815. doi:10.1128/JB.187.19.6804-6815.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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

    Article  CAS  PubMed  Google Scholar 

  115. 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

    Article  CAS  PubMed  Google Scholar 

  116. 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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  118. 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

    Article  CAS  PubMed  Google Scholar 

  119. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schuster S, Kohler S, Buck A, Dambacher C, Konig A, Bohnert JA, Kern WV (2014) Random mutagenesis of the multidrug transporter AcrB from Escherichia coli for identification of putative target residues of efflux pump inhibitors. Antimicrob Agents Chemother 58:6870–6878. doi:10.1128/AAC.03775-14

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Fuller RW, Mason NR, Snoddy HD, Perry KW (1986) 1-(1-Naphthyl)piperazine, a central serotonin agonist. Res Commun Chem Pathol Pharmacol 51:37–45

    CAS  PubMed  Google Scholar 

  122. Schumacher A, Steinke P, Bohnert JA, Akova M, Jonas D, Kern WV (2006) Effect of 1-(1-naphthylmethyl)-piperazine, a novel putative efflux pump inhibitor, on antimicrobial drug susceptibility in clinical isolates of Enterobacteriaceae other than Escherichia coli. J Antimicrob Chemother 57:344–348. doi:10.1093/jac/dki446

    Article  CAS  PubMed  Google Scholar 

  123. Schumacher A, Trittler R, Bohnert JA, Kummerer K, Pages J-M, Kern WV (2007) Intracellular accumulation of linezolid in Escherichia coli, Citrobacter freundii and Enterobacter aerogenes: role of enhanced efflux pump activity and inactivation. J Antimicrob Chemother 59:1261–1264. doi:10.1093/jac/dkl380

    Article  CAS  PubMed  Google Scholar 

  124. Pannek S, Higgins PG, Steinke P, Jonas D, Akova M, Bohnert JA, Seifert H, Kern WV (2006) Multidrug efflux inhibition in Acinetobacter baumannii: comparison between 1-(1-naphthylmethyl)-piperazine and phenyl-arginine-β-naphthylamide. J Antimicrob Chemother 57:970–974. doi:10.1093/jac/dkl081

    Article  CAS  PubMed  Google Scholar 

  125. Buckley AM, Webber MA, Cooles S, Randall LP, La Ragione RM, Woodward MJ, Piddock LJ (2006) The AcrAB-TolC efflux system of Salmonella enterica serovar Typhimurium plays a role in pathogenesis. Cell Microbiol 8:847–856. doi:10.1111/j.1462-5822.2005.00671.x

    Article  CAS  PubMed  Google Scholar 

  126. Bina XR, Lavine CL, Miller MA, Bina JE (2008) The AcrAB RND efflux system from the live vaccine strain of Francisella tularensis is a multiple drug efflux system that is required for virulence in mice. FEMS Microbiol Lett 279:226–233. doi:10.1111/j.1574-6968.2007.01033.x

    Article  CAS  PubMed  Google Scholar 

  127. Padilla E, Llobet E, Doménech-Sánchez A, Martínez-Martínez L, Bengoechea JA, Albertí S (2010) Klebsiella pneumoniae AcrAB efflux pump contributes to antimicrobial resistance and virulence. Antimicrob Agents Chemother 54:177–183. doi:10.1128/AAC.00715-09

    Article  CAS  PubMed  Google Scholar 

  128. 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

    Article  CAS  PubMed  Google Scholar 

  129. Bina XR, Philippart JA, Bina JE (2009) Effect of the efflux inhibitors 1-(1-naphthylmethyl)-piperazine and phenyl-arginine-β-naphthylamide on antimicrobial susceptibility and virulence factor production in Vibrio cholerae. J Antimicrob Chemother 63:103–108. doi:10.1093/jac/dkn466

    Article  CAS  PubMed  Google Scholar 

  130. Kvist M, Hancock V, Klemm P (2008) Inactivation of efflux pumps abolishes bacterial biofilm formation. Appl Environ Microbiol 74:7376–7382. doi:10.1128/AEM.01310-08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bohnert JA, Schuster S, Kern WV, 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. Antimicrob Agents Chemother 60:1974–1983. doi:10.1128/AAC.02436-15

    Google Scholar 

  136. Nakayama K, Ishida Y, Ohtsuka M, Kawato H, Yoshida K, Yokomizo Y, Hosono S, Ohta T et al (2003) MexAB-OprM-specific efflux pump inhibitors in Pseudomonas aeruginosa. Part 1: discovery and early strategies for lead optimization. Bioorg Med Chem Lett 13:4201–4204. doi:10.1016/j.bmcl.2003.07.024

    Article  CAS  PubMed  Google Scholar 

  137. Yoshida K, Nakayama K, Ohtsuka M, Kuru N, Yokomizo Y, Sakamoto A, Takemura M, Hoshino K et al (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 15:7087–7097. doi:10.1016/j.bmc.2007.07.039

    Google Scholar 

  138. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Thorarensen A, Presley-Bodnar AL, Marotti KR, Boyle TP, Heckaman CL, Bohanon MJ, Tomich PK, Zurenko GE et al (2001) 3-Arylpiperidines as potentiators of existing antibacterial agents. Bioorg Med Chem Lett 11:1903–1906. doi:10.1016/S0960-894X(01)00330-4

    Article  CAS  PubMed  Google Scholar 

  140. 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

    Article  PubMed  CAS  Google Scholar 

  141. Chevalier J, Bredin J, Mahamoud A, Malléa M, Barbe J, Pagès JM (2004) Inhibitors of antibiotic efflux in resistant Enterobacter aerogenes and Klebsiella pneumoniae strains. Antimicrob Agents Chemother 48:1043–1046. doi:10.1128/AAC.48.3.1043-1046.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ghisalberti D, Mahamoud A, Chevalier J, Baitiche M, Martino M, Pagès JM, Barbe J (2006) Chloroquinolines block antibiotic efflux pumps in antibiotic-resistant Enterobacter aerogenes isolates. Int J Antimicrob Agents 27:565–569. doi:10.1016/j.ijantimicag.2006.03.010

    Article  CAS  PubMed  Google Scholar 

  143. Mahamoud A, Chevalier J, Baitiche M, Adam E, Pagès JM (2011) An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates. Microbiology 157:566–571. doi:10.1099/mic.0.045716-0

    Google Scholar 

  144. Handzlik J, Szymanska E, Alibert S, Chevalier J, Otrebska E, Pekala E, Pagès JM, Kiec-Kononowicz K (2013) Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin. Bioorg Med Chem 21:135–145. doi:10.1016/j.bmc.2012.10.053

    Google Scholar 

  145. 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

    Article  CAS  PubMed  Google Scholar 

  146. Takacs D, Cerca P, Martins A, Riedl Z, Hajos G, Molnar J, Viveiros M, Couto I et al (2011) Evaluation of forty new phenothiazine derivatives for activity against intrinsic efflux pump systems of reference Escherichia coli, Salmonella Enteritidis, Enterococcus faecalis and Staphylococcus aureus strains. In Vivo 25:719–724

    CAS  PubMed  Google Scholar 

  147. Bailey AM, Ivens A, Kingsley R, Cottell JL, Wain J, Piddock LJ (2010) RamA, a member of the AraC/XylS family, influences both virulence and efflux in Salmonella enterica serovar Typhimurium. J Bacteriol 192:1607–1616. doi:10.1128/JB.01517-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kristiansen JE, Thomsen VF, Martins A, Viveiros M, Amaral L (2010) Non-antibiotics reverse resistance of bacteria to antibiotics. In Vivo 24:751–754

    CAS  PubMed  Google Scholar 

  149. Bohnert JA, Schuster S, Kern WV (2013) Pimozide inhibits the AcrAB-TolC efflux pump in Escherichia coli. Open Microbiol J 7:83–86. doi:10.2174/1874285801307010083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Bohnert JA, Szymaniak-Vits M, Schuster S, Kern WV (2011) Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli. J Antimicrob Chemother 66:2057–2060. doi:10.1093/jac/dkr258

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Tavio MM, Vila J, Perilli M, Casanas LT, Macia L, Amicosante G, Jimenez de Anta MT (2004) Enhanced active efflux, repression of porin synthesis and development of Mar phenotype by diazepam in two enterobacteria strains. J Med Microbiol 53:1119–1122. doi:10.1099/jmm.0.45613-0

    Article  CAS  PubMed  Google Scholar 

  153. Lawler AJ, Ricci V, Busby SJ, Piddock LJ (2013) Genetic inactivation of acrAB or inhibition of efflux induces expression of ramA. J Antimicrob Chemother 68:1551–1557. doi:10.1093/jac/dkt069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Vidal-Aroca F, Meng A, Minz T, Page MG, Dreier J (2009) Use of resazurin to detect mefloquine as an efflux-pump inhibitor in Pseudomonas aeruginosa and Escherichia coli. J Microbiol Methods 79:232–237. doi:10.1016/j.mimet.2009.09.021

    Article  CAS  PubMed  Google Scholar 

  155. Martins A, Spengler G, Rodrigues L, Viveiros M, Ramos J, Martins M, Couto I, Fanning S et al (2009) pH Modulation of efflux pump activity of multi-drug resistant Escherichia coli: protection during its passage and eventual colonization of the colon. PLoS One 4:e6656. doi:10.1371/journal.pone.0006656

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Tyski S (2003) Non-antibiotics – drugs with additional antimicrobial activity. Acta Pol Pharm 60:401–404

    CAS  PubMed  Google Scholar 

  157. Kumar KA, Ganguly K, Mazumdar K, Dutta NK, Dastidar SG, Chakrabarty AN (2003) Amlodipine: a cardiovascular drug with powerful antimicrobial property. Acta Microbiol Pol 52:285–292

    CAS  PubMed  Google Scholar 

  158. Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen JE, Molnar J, Martins M, Amaral L (2007) Potential management of resistant microbial infections with a novel non-antibiotic: the anti-inflammatory drug diclofenac sodium. Int J Antimicrob Agents 30:242–249. doi:10.1016/j.ijantimicag.2007.04.018

    Article  CAS  PubMed  Google Scholar 

  159. Ejim L, Farha MA, Falconer SB, Wildenhain J, Coombes BK, Tyers M, Brown ED, Wright GD (2011) Combinations of antibiotics and nonantibiotic drugs enhance antimicrobial efficacy. Nat Chem Biol 7:348–350. doi:10.1038/nchembio.559

    Article  CAS  PubMed  Google Scholar 

  160. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Piddock LJ, Garvey MI, Rahman MM, Gibbons S (2010) Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother 65:1215–1223. doi:10.1093/jac/dkq079

    Article  CAS  PubMed  Google Scholar 

  162. Mandal S, Mandal MD, Pal NK (2004) Synergism of ciprofloxacin and trimethoprim against Salmonella enterica serovar Typhi isolates showing reduced susceptibility to ciprofloxacin. Chemotherapy 50:152–154. doi:10.1159/000077890

    Article  CAS  PubMed  Google Scholar 

  163. Klinker H, Langmann P, Zilly M, Richter E (1998) Drug monitoring during the treatment of AIDS-associated Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole. J Clin Pharm Ther 23:149–154. doi:10.1046/j.1365-2710.1998.00152.x

    Article  CAS  PubMed  Google Scholar 

  164. Ahmad I, Aqil F (2007) In vitro efficacy of bioactive extracts of 15 medicinal plants against ESBL-producing multidrug-resistant enteric bacteria. Microbiol Res 162:264–275. doi:10.1016/j.micres.2006.06.010

    Google Scholar 

  165. Nweze EI, Eze EE (2009) Justification for the use of Ocimum gratissimum L in herbal medicine and its interaction with disc antibiotics. BMC Complement Altern Med 9:37. doi:10.1186/1472-6882-9-37

    Article  PubMed  PubMed Central  Google Scholar 

  166. Garvey MI, Rahman MM, Gibbons S, Piddock LJ (2011) Medicinal plant extracts with efflux inhibitory activity against Gram-negative bacteria. Int J Antimicrob Agents 37:145–151. doi:10.1016/j.ijantimicag.2010.10.027

    Article  CAS  PubMed  Google Scholar 

  167. Zhou X, Jia F, Liu X, Wang Y (2012) Total alkaloids of Sophorea alopecuroides-induced down-regulation of AcrAB-TolC efflux pump reverses susceptibility to ciprofloxacin in clinical multidrug resistant Escherichia coli isolates. Phytother Res 26:1637–1643. doi:10.1002/ptr.4623

    Article  CAS  PubMed  Google Scholar 

  168. Touani FK, Seukep AJ, Djeussi DE, Fankam AG, Noumedem JA, Kuete V (2014) Antibiotic-potentiation activities of four Cameroonian dietary plants against multidrug-resistant Gram-negative bacteria expressing efflux pumps. BMC Complement Altern Med 14:258. doi:10.1186/1472-6882-14-258

    Article  PubMed  PubMed Central  Google Scholar 

  169. Njimoh DL, Assob JC, Mokake SE, Nyhalah DJ, Yinda CK, Sandjon B (2015) Antimicrobial activities of a plethora of medicinal plant extracts and hydrolates against human pathogens and their potential to reverse antibiotic resistance. Int J Microbiol 2015:547156. doi:10.1155/2015/547156

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Lee MD, Galazzo JL, Staley AL, Lee JC, Warren MS, Fuernkranz H, Chamberland S, Lomovskaya O et al (2001) Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco 56:81–85. doi:10.1016/S0014-827X(01)01002-3

    Article  CAS  PubMed  Google Scholar 

  171. Dwivedi GR, Gupta S, Maurya A, Tripathi S, Sharma A, Darokar MP, Srivastava SK (2015) Synergy potential of indole alkaloids and its derivative against drug-resistant Escherichia coli. Chem Biol Drug Des 86:1471–1481. doi:10.1111/cbdd.12613

    Article  CAS  PubMed  Google Scholar 

  172. Li B, Yao Q, Pan XC, Wang N, Zhang R, Li J, Ding G, Liu X et al (2011) Artesunate enhances the antibacterial effect of β-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC. J Antimicrob Chemother 66:769–777. doi:10.1093/jac/dkr017

    Article  CAS  PubMed  Google Scholar 

  173. Lorenzi V, Muselli A, Bernardini AF, Berti L, Pagès JM, Amaral L, Bolla JM (2009) Geraniol restores antibiotic activities against multidrug-resistant isolates from Gram-negative species. Antimicrob Agents Chemother 53:2209–2211. doi:10.1128/AAC.00919-08

    Google Scholar 

  174. Brunel JM, Lieutaud A, Lome V, Pagès JM, Bolla JM (2013) Polyamino geranic derivatives as new chemosensitizers to combat antibiotic resistant Gram-negative bacteria. Bioorg Med Chem 21:1174–1179. doi:10.1016/j.bmc.2012.12.030

    Article  CAS  PubMed  Google Scholar 

  175. 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

    Google Scholar 

  176. Negi N, Prakash P, Gupta ML, Mohapatra TM (2014) Possible role of curcumin as an efflux pump inhibitor in multidrug resistant clinical isolates of Pseudomonas aeruginosa. J Clin Diagn Res 8:DC04–DC07. doi:10.7860/JCDR/2014/8329.4965

    PubMed  PubMed Central  Google Scholar 

  177. Li X-Z, Nikaido H, Poole K (1995) Role of MexA-MexB-OprM in antibiotic efflux in Pseudomonas aeruginosa. Antimicrob Agents Chemother 39:1948–1953. doi:10.1128/AAC.39.9.1948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Salem M, Rohani S, Gillies ER (2014) Curcumin, a promising anti-cancer therapeutic: a review of its chemical properties, bioactivity and approaches to cancer cell delivery. RSC Adv 4:10815–10829. doi:10.1039/C3RA46396F

    Article  CAS  Google Scholar 

  179. Ohene‐Agyei T, Mowla R, Rahman T, Venter H (2014) Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump. MicrobiologyOpen 3:885–896. doi:10.1002/mbo3.212

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Medical Microbiology, University Hospital, Friedrich-Schiller-University Jena, Jena, Germany

    Jürgen A. Bohnert

  2. Center for Infectious Diseases and Travel Medicine, University Hospital, Freiburg, Germany

    Winfried V. Kern

  3. Department of Medicine, Albert-Ludwigs-University Hospital, Medical Center, Freiburg, Germany

    Winfried V. Kern

Authors
  1. Jürgen A. Bohnert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Winfried V. Kern
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jürgen A. Bohnert .

Editor information

Editors and Affiliations

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

    Xian-Zhi Li

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

    Christopher A. Elkins

  3. University of Oklahoma, Norman, Oklahoma, USA

    Helen I. Zgurskaya

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Bohnert, J.A., Kern, W.V. (2016). Antimicrobial Drug Efflux Pump Inhibitors. In: Li, XZ., Elkins, C., Zgurskaya, H. (eds) Efflux-Mediated Antimicrobial Resistance in Bacteria. Adis, Cham. https://doi.org/10.1007/978-3-319-39658-3_29

Download citation

Publish with us

Policies and ethics

Search

Navigation