EFFLUX PUMP INHIBITORS: PAVING THE WAY FROM RESEARCH BENCH TO BEDSIDE BATTLE AGAINST BACTERIAL PATHOGENS
Main Article Content
Keywords
Antibiotics, efflux pumps, multiple drug resistance, pathogens, therapeutics
Abstract
It was thought that bacterial illnesses would go extinct with the development of antibiotics. Instead, it caused microorganisms with defence mechanisms against antibiotics to be selected for and evolve. Antibiotic efflux is a key process by which bacteria use unique transporter proteins known as efflux pumps to pump antibiotics out of their cellular interior and into the surrounding environment. Given the scarcity of new antibiotics, inhibiting these pumps appears to be a desirable tactic. Efflux pump inhibitors (EPIs) are molecules that have the potential to block these pumps. They are being considered as possible therapeutic agents that could reactivate antibiotics that have lost their effectiveness against bacterial diseases. EPIs are characterised by their general efflux inhibition methods.
References
1. Lewis K. Antibiotics: Recover the lost art of drug discovery. Nature. 2012;485:439–40.
2. Ory EM, Yow EM. The use and abuse of the broad spectrum antibiotics. JAMA. 1963;185:273–9.
3. Fleming-Dutra KE, Hersh AL, Shapiro DJ, Bartoces M, Enns EA, File TM., Jr Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA. 2016;315:1864–73.
4. Haque M, Sartelli M, McKimm J, Abu Bakar M. Health care-associated infections-an overview. Infect Drug Resist. 2018;11:2321–33.
5. Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. P T. 2015;40:277–83.
6. Falagas ME, Karageorgopoulos DE. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: Need for international harmonization in terminology. Clin Infect Dis. 2008;46:1121–2.
7. Hoffman SJ, Outterson K. Introduction: What will it take to address the global threat of antibiotic resistance? J Law Med Ethics. 2015;43(Suppl 3):6–11.
8. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015;13:42–51.
9. Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev. 2006;19:382–402.
10. Schindler BD, Kaatz GW. Multidrug efflux pumps of Gram-positive bacteria. Drug Resist Updat. 2016;27:1–3.
11. Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev. 2015;28:337–418.
12. Blair JM, Richmond GE, Piddock LJ. Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol. 2014;9:1165–77.
13. Webber MA, Piddock LJ. The importance of efflux pumps in bacterial antibiotic resistance. J Antimicrob Chemother. 2003;51:9–11.
14. Sharma A, Sharma R, Bhattacharyya T, Bhando T, Pathania R. Fosfomycin resistance in Acinetobacter baumannii is mediated by efflux through a major facilitator superfamily (MFS) transporter-AbaF. J Antimicrob Chemother. 2017;72:68–74.
15. Costa SS, Ntokou E, Martins A, Viveiros M, Pournaras S, Couto I, et al. Identification of the plasmid-encoded QacA efflux pump gene in meticillin-resistant Staphylococcus aureus (MRSA) strain HPV107, a representative of the MRSA iberian clone. Int J Antimicrob Agents. 2010;36:557–61.
16. Santagati M, Iannelli F, Cascone C, Campanile F, Oggioni MR, Stefani S, et al. The novel conjugative transposon TN1207.3 carries the macrolide efflux gene mef(A) in Streptococcus pyogenes. Microb Drug Resist. 2003;9:243–7.
17. Piddock LJ. Multidrug-resistance efflux pumps – Not just for resistance. Nat Rev Microbiol. 2006;4:629–36.
18. Bhardwaj AK, Mohanty P. Bacterial efflux pumps involved in multidrug resistance and their inhibitors: Rejuvinating the antimicrobial chemotherapy. Recent Pat Antiinfect Drug Discov. 2012;7:73–89.
19. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy. Antimicrob Agents Chemother. 2001;45:105–16.
20. Kothari A, Kherdekar R, Mago V, Uniyal M, Mamgain G, Kalia RB, Kumar S, Jain N, Pandey A, Omar BJ. Age of Antibiotic Resistance in MDR/XDR Clinical Pathogen of Pseudomonas aeruginosa. Pharmaceuticals. 2023 Aug 30;16(9):1230.
21. Anoushiravani M, Falsafi T, Niknam V. Proton motive force-dependent efflux of tetracycline in clinical isolates of Helicobacter pylori. J Med Microbiol. 2009;58:1309–13.
22. Fenosa A, Fusté E, Ruiz L, Veiga-Crespo P, Vinuesa T, Guallar V, et al. Role of tolC in Klebsiella oxytoca resistance to antibiotics. J Antimicrob Chemother. 2009;63:668–74.
23. Osei Sekyere J, Amoako DG. Carbonyl cyanide m-chlorophenylhydrazine (CCCP) reverses resistance to colistin, but not to carbapenems and tigecycline in multidrug-resistant Enterobacteriaceae. Front Microbiol. 2017;8:228.
24. Vargiu AV, Nikaido H. Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Natl Acad Sci. 2012;109:20637–42.
25. Gupta S, Cohen KA, Winglee K, Maiga M, Diarra B, Bishai WR. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58:574–6.
26. Singh M, Jadaun GP, Ramdas, Srivastava K, Chauhan V, Mishra R, et al. Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates. Indian J Med Res. 2011;133:535–40.
27. Radchenko M, Symersky J, Nie R, Lu M. Structural basis for the blockade of MATE multidrug efflux pumps. Nat Commun. 2015;6:7995.
28. Bohnert JA, Kern WV. Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother. 2005;49:849–52.
29. Vargiu AV, Ruggerone P, Opperman TJ, Nguyen ST, Nikaido H. Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob Agents Chemother. 2014;58:6224–34.
30. Stavri M, Piddock LJ, Gibbons S. Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother. 2007;59:1247–60.
31. Gibbons S, Oluwatuyi M, Kaatz GW. A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus. J Antimicrob Chemother. 2003;51:13–7.
32. Pfeifer HJ, Greenblatt DK, Koch-Wester J. Clinical toxicity of reserpine in hospitalized patients: A report from the Boston collaborative drug surveillance program. Am J Med Sci. 1976;271:269–76.
33. Kumar A, Khan IA, Koul S, Koul JL, Taneja SC, Ali I, et al. Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus. J Antimicrob Chemother. 2008;61:1270–6.
34. Sharma S, Kumar M, Sharma S, Nargotra A, Koul S, Khan IA. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother. 2010;65:1694–701.
35. Kothari A, Jain N, Kishor Kumar S, Kumar A, Kaushal K, Kaur S, Pandey A, Gaurav A, Omar BJ. Potential synergistic antibiotic combinations against fluoroquinolone-resistant Pseudomonas aeruginosa. Pharmaceuticals. 2022 Feb 18;15(2):243.
36. Fujita M, Shiota S, Kuroda T, Hatano T, Yoshida T, Mizushima T, et al. Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol. 2005;49:391–6.
37. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K. Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5’-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci. 2000;97:1433–7.
38. Morel C, Stermitz FR, Tegos G, Lewis K. Isoflavones as potentiators of antibacterial activity. J Agric Food Chem. 2003;51:5677–9.
39. Gibbons S, Moser E, Kaatz GW. Catechin gallates inhibit multidrug resistance (MDR) in Staphylococcus aureus. Planta Med. 2004;70:1240–2.
40. Sudano Roccaro A, Blanco AR, Giuliano F, Rusciano D, Enea V. Epigallocatechin-gallate enhances the activity of tetracycline in staphylococci by inhibiting its efflux from bacterial cells. Antimicrob Agents Chemother. 2004;48:1968–73.
41. Oluwatuyi M, Kaatz GW, Gibbons S. Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry. 2004;65:3249–54.
42. Lorenzi V, Muselli A, Bernardini AF, Berti L, Pagès JM, Amaral L, et al. Geraniol restores antibiotic activities against multidrug-resistant isolates from Gram-negative species. Antimicrob Agents Chemother. 2009;53:2209–11.
43. Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol. 2015;6:421.
44. Chevalier J, Atifi S, Eyraud A, Mahamoud A, Barbe J, Pagès JM. New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains. J Med Chem. 2001;44:4023–6.
45. Pradel E, Pagès JM. The AcrAB-tolC efflux pump contributes to multidrug resistance in the nosocomial pathogen Enterobacter aerogenes. Antimicrob Agents Chemother. 2002;46:2640–3.
46. Sabatini S, Gosetto F, Manfroni G, Tabarrini O, Kaatz GW, Patel D, et al. 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. 2011;54:5722–36.
47. Thorarensen A, Presley-Bodnar AL, Marotti KR, Boyle TP, Heckaman CL, Bohanon MJ, et al. 3-arylpiperidines as potentiators of existing antibacterial agents. Bioorg Med Chem Lett. 2001;11:1903–6.
48. Kaatz GW, Moudgal VV, Seo SM, Hansen JB, Kristiansen JE. Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. Int J Antimicrob Agents. 2003;22:254–61.
49. Mahmood HY, Jamshidi S, Sutton JM, Rahman KM. Current advances in developing inhibitors of bacterial multidrug efflux pumps. Curr Med Chem. 2016;23:1062–81.
50. Zechini B, Versace I. Inhibitors of multidrug resistant efflux systems in bacteria. Recent Pat Antiinfect Drug Discov. 2009;4:37–50.
51. Piddock LJ, Garvey MI, Rahman MM, Gibbons S. Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother. 2010;65:1215–23.
52. Neyfakh AA, Bidnenko VE, Chen LB. Efflux-mediated multidrug resistance in Bacillus subtilis: Similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci U S A. 1991;88:4781–5.
53. Song L, Wu X. Development of efflux pump inhibitors in antituberculosis therapy. Int J Antimicrob Agents. 2016;47:421–9.
54. Fiamegos YC, Kastritis PL, Exarchou V, Han H, Bonvin AM, Vervoort J, et al. Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against Gram-positive pathogenic bacteria. PLoS One. 2011;6:e18127.
55. Joshi P, Singh S, Wani A, Sharma S, Jain SK, Singh B, et al. Osthol and curcumin as inhibitors of human Pgp and multidrug efflux pumps of Staphylococcus aureus: Reversing the resistance against frontline antibacterial drugs. Med Chem Commun. 2014;5:1540–7.
56. Holler JG, Christensen SB, Slotved HC, Rasmussen HB, Gúzman A, Olsen CE, et al. Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue nees. J Antimicrob Chemother. 2012;67:1138–44.
57. Michalet S, Cartier G, David B, Mariotte AM, Dijoux-franca MG, Kaatz GW, et al. N-caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors. Bioorg Med Chem Lett. 2007;17:1755–8.
58. Li B, Yao Q, Pan XC, Wang N, Zhang R, Li J, et al. Artesunate enhances the antibacterial effect of {beta|-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC. J Antimicrob Chemother. 2011;66:769–77.
59. Chérigo L, Pereda-Miranda R, Fragoso-Serrano M, Jacobo-Herrera N, Kaatz GW, Gibbons S. Inhibitors of bacterial multidrug efflux pumps from the resin glycosides of Ipomoea murucoides. J Nat Prod. 2008;71:1037–45.
60. Rana T, Singh S, Kaur N, Pathania K, Farooq U. A review on efflux pump inhibitors of medically important bacteria from plant sources. Int J Pharm Sci Rev Res. 2014;26:101–11.
61. Roy SK, Kumari N, Pahwa S, Agrahari UC, Bhutani KK, Jachak SM, et al. NorA efflux pump inhibitory activity of coumarins from Mesua ferrea. Fitoterapia. 2013;90:140–50.
62. Stermitz FR, Scriven LN, Tegos G, Lewis K. Two flavonols from Artemisa annua which potentiate the activity of berberine and norfloxacin against a resistant strain of Staphylococcus aureus. Planta Med. 2002;68:1140–1.
63. Chan BC, Ip M, Gong H, Lui SL, See RH, Jolivalt C, et al. Synergistic effects of diosmetin with erythromycin against ABC transporter over-expressed methicillin-resistant Staphylococcus aureus (MRSA) RN4220/pUL5054 and inhibition of MRSA pyruvate kinase. Phytomedicine. 2013;20:611–4.
64. Roy SK, Pahwa S, Nandanwar H, Jachak SM. Phenylpropanoids of Alpinia galangal as efflux pump inhibitors in Mycobacterium smegmatis mc2 155. Fitoterapia. 2012;83:1248–55.
65. Shiu WK, Malkinson JP, Rahman MM, Curry J, Stapleton P, Gunaratnam M, et al. A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus. Int J Antimicrob Agents. 2013;42:513–8.
66. Chovanová R, Mezovská J, Vaverková Š, Mikulášová M. The inhibition the Tet(K) efflux pump of tetracycline resistant Staphylococcus epidermidis by essential oils from three Salvia species. Lett Appl Microbiol. 2015;61:58–62.
67. Bruhn DF, Scherman MS, Liu J, Scherbakov D, Meibohm B, Böttger EC, et al. In vitro and in vivo evaluation of synergism between anti-tubercular spectinamides and non-classical tuberculosis antibiotics. Sci Rep. 2015;5:13985.
68. Smith EC, Williamson EM, Wareham N, Kaatz GW, Gibbons S. Antibacterials and modulators of bacterial resistance from the immature cones of Chamaecyparis lawsoniana. Phytochemistry. 2007;68:210–7.
69. Smith EC, Kaatz GW, Seo SM, Wareham N, Williamson EM, Gibbons S. The phenolic diterpene totarol inhibits multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother. 2007;51:4480–3.
70. Singh S, Kalia NP, Joshi P, Kumar A, Sharma PR, Kumar A, et al. Boeravinone B, A novel dual inhibitor of NorA bacterial efflux pump of Staphylococcus aureus and human P-glycoprotein, reduces the biofilm formation and intracellular invasion of bacteria. Front Microbiol. 2017;8:1868.
71. Limaverde PW, Campina FF, da Cunha FAB, Crispim FD, Figueredo FG, Lima LF, et al. Inhibition of the TetK efflux-pump by the essential oil of Chenopodium ambrosioides L. and α-terpinene against Staphylococcus aureus IS-58. Food Chem Toxicol. 2017;109:957–61.
72. Kakarla P, Floyd J, Mukherjee M, Devireddy AR, Inupakutika MA, Ranweera I, et al. Inhibition of the multidrug efflux pump LmrS from Staphylococcus aureus by cumin spice Cuminum cyminum. Arch Microbiol. 2017;199:465–74.
73. Fazly Bazzaz BS, Iranshahi M, Naderinasab M, Hajian S, Sabeti Z, Masumi E. Evaluation of the effects of galbanic acid from Ferula szowitsiana and conferol from F. badrakema, as modulators of multi-drug resistance in clinical isolates of Escherichia coli and Staphylococcus aureus. Res Pharm Sci. 2010;5:21–8.
74. Tintino SR, Morais-Tintino CD, Campina FF, Costa MDS, Menezes IRA, de Matos YMLS, et al. Tannic acid affects the phenotype of Staphylococcus aureus resistant to tetracycline and erythromycin by inhibition of efflux pumps. Bioorg Chem. 2017;74:197–200.
75. Siriyong T, Srimanote P, Chusri S, Yingyongnarongkul BE, Suaisom C, Tipmanee V, et al. Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. BMC Complement Altern Med. 2017;17:405.
76. Siriyong T, Chusri S, Srimanote P, Tipmanee V, Voravuthikunchai SP. Holarrhena antidysenterica extract and its steroidal alkaloid, conessine, as resistance-modifying agents against extensively drug-resistant Acinetobacter baumannii. Microb Drug Resist. 2016;22:273–82.
77. Chan BC, Han XQ, Lui SL, Wong CW, Wang TB, Cheung DW, et al. Combating against methicillin-resistant Staphylococcus aureus – Two fatty acids from purslane (Portulaca oleracea L.) exhibit synergistic effects with erythromycin. J Pharm Pharmacol. 2015;67:107–16.
78. Falcão-Silva VS, Silva DA, Souza Mde F, Siqueira-Junior JP. Modulation of drug resistance in Staphylococcus aureus by a kaempferol glycoside from Herissantia tiubae (Malvaceae) Phytother Res. 2009;23:1367–70.
79. Kalia NP, Mahajan P, Mehra R, Nargotra A, Sharma JP, Koul S, et al. Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. J Antimicrob Chemother. 2012;67:2401–8.
80. Gupta VK, Tiwari N, Gupta P, Verma S, Pal A, Srivastava SK, et al. A clerodane diterpene from Polyalthia longifolia as a modifying agent of the resistance of methicillin resistant Staphylococcus aureus. Phytomedicine. 2016;23:654–61.
81. Martins A, Vasas A, Viveiros M, Molnár J, Hohmann J, Amaral L, et al. Antibacterial properties of compounds isolated from Carpobrotus edulis. Int J Antimicrob Agents. 2011;37:438–44.
82. Bharate JB, Singh S, Wani A, Sharma S, Joshi P, Khan IA, et al. Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus nor A efflux pump. Org Biomol Chem. 2015;13:5424–31.
83. Schindler BD, Jacinto P, Kaatz GW. Inhibition of drug efflux pumps in Staphylococcus aureus: Current status of potentiating existing antibiotics. Future Microbiol. 2013;8:491–507.
84. Holler JG, Slotved HC, Mølgaard P, Olsen CE, Christensen SB. Chalcone inhibitors of the NorA efflux pump in Staphylococcus aureus whole cells and enriched everted membrane vesicles. Bioorg Med Chem. 2012;20:4514–21.
85. Haynes KM, Abdali N, Jhawar V, Zgurskaya HI, Parks JM, Green AT, et al. Identification and structure-activity relationships of novel compounds that potentiate the activities of antibiotics in Escherichia coli. J Med Chem. 2017;60:6205–19.
86. Cortez-Cordova J, Kumar A. Activity of the efflux pump inhibitor phenylalanine-arginine β-naphthylamide against the AdeFGH pump of Acinetobacter baumannii. Int J Antimicrob Agents. 2011;37:420–4.
87. Bohnert JA, Schuster S, Kern WV, Karcz T, Olejarz A, Kaczor A, et al. 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. 2016;60:1974–83.
88. Machado D, Fernandes L, Costa SS, Cannalire R, Manfroni G, Tabarrini O, et al. Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R against Escherichia coli. Peer J. 2017;5:e3168.
89. Handzlik J, Szymańska E, Alibert S, Chevalier J, Otrębska E, Pękala E, et al. Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin. Bioorg Med Chem. 2013;21:135–45.
90. Nelson ML, Levy SB. Reversal of tetracycline resistance mediated by different bacterial tetracycline resistance determinants by an inhibitor of the Tet(B) antiport protein. Antimicrob Agents Chemother. 1999;43:1719–24.
91. Tintino SR, Morais-Tintino CD, Campina FF, Pereira RL, Costa Mdo S, Braga MF, et al. Action of cholecalciferol and alpha-tocopherol on Staphylococcus aureus efflux pumps. EXCLI J. 2016;15:315–22.
92. Simons SO, Kristiansen JE, Hajos G, van der Laan T, Molnár J, Boeree MJ, et al. Activity of the efflux pump inhibitor SILA 421 against drug-resistant tuberculosis. Int J Antimicrob Agents. 2013;41:488–9.
93. Sabatini S, Kaatz GW, Rossolini GM, Brandini D, Fravolini A. From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. J Med Chem. 2008;51:4321–30.
94. Song Y, Qin R, Pan X, Ouyang Q, Liu T, Zhai Z, et al. Design of new antibacterial enhancers based on AcrB's structure and the evaluation of their antibacterial enhancement activity. Int J Mol Sci. 2016;17 pii: E1934.
95. Costa LM, de Macedo EV, Oliveira FA, Ferreira JH, Gutierrez SJ, Peláez WJ, et al. Inhibition of the NorA efflux pump of Staphylococcus aureus by synthetic riparins. J Appl Microbiol. 2016;121:1312–22.
96. Coêlho ML, Ferreira JH, de Siqueira Júnior JP, Kaatz GW, Barreto HM, de Carvalho Melo Cavalcante AA, et al. Inhibition of the NorA multi-drug transporter by oxygenated monoterpenes. Microb Pathog. 2016;99:173–7.
97. Wani NA, Singh S, Farooq S, Shankar S, Koul S, Khan IA, et al. Amino acid amides of piperic acid (PA) and 4-ethylpiperic acid (EPA) as NorA efflux pump inhibitors of Staphylococcus aureus. Bioorg Med Chem Lett. 2016;26:4174–8.
98. Fontaine F, Héquet A, Voisin-Chiret AS, Bouillon A, Lesnard A, Cresteil T, et al. Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: Study of 6-substituted pyridine-3-boronic acid derivatives. Eur J Med Chem. 2015;95:185–98.
99. Zhang J, Sun Y, Wang Y, Lu M, He J, Liu J, et al. Non-antibiotic agent ginsenoside 20(S)-rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor. Eur J Pharmacol. 2014;740:277–84.
100. Bohnert JA, Schuster S, Kern WV. Pimozide inhibits the AcrAB-tolC efflux pump in Escherichia coli. Open Microbiol J. 2013;7:83–6.
101. Lee MD, Galazzo JL, Staley AL, Lee JC, Warren MS, Fuernkranz H, et al. Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco. 2001;56:81–5.
102. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic – A vision for applied use. Biochem Pharmacol. 2006;71:910–8.
103. Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA. 2013;310:2544–53.
104. Nakajima A, Sugimoto Y, Yoneyama H, Nakae T. High-level fluoroquinolone resistance in Pseudomonas aeruginosa due to interplay of the MexAB-oprM efflux pump and the DNA gyrase mutation. Microbiol Immunol. 2002;46:391–5
2. Ory EM, Yow EM. The use and abuse of the broad spectrum antibiotics. JAMA. 1963;185:273–9.
3. Fleming-Dutra KE, Hersh AL, Shapiro DJ, Bartoces M, Enns EA, File TM., Jr Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA. 2016;315:1864–73.
4. Haque M, Sartelli M, McKimm J, Abu Bakar M. Health care-associated infections-an overview. Infect Drug Resist. 2018;11:2321–33.
5. Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. P T. 2015;40:277–83.
6. Falagas ME, Karageorgopoulos DE. Pandrug resistance (PDR), extensive drug resistance (XDR), and multidrug resistance (MDR) among Gram-negative bacilli: Need for international harmonization in terminology. Clin Infect Dis. 2008;46:1121–2.
7. Hoffman SJ, Outterson K. Introduction: What will it take to address the global threat of antibiotic resistance? J Law Med Ethics. 2015;43(Suppl 3):6–11.
8. Blair JM, Webber MA, Baylay AJ, Ogbolu DO, Piddock LJ. Molecular mechanisms of antibiotic resistance. Nat Rev Microbiol. 2015;13:42–51.
9. Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin Microbiol Rev. 2006;19:382–402.
10. Schindler BD, Kaatz GW. Multidrug efflux pumps of Gram-positive bacteria. Drug Resist Updat. 2016;27:1–3.
11. Li XZ, Plésiat P, Nikaido H. The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria. Clin Microbiol Rev. 2015;28:337–418.
12. Blair JM, Richmond GE, Piddock LJ. Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance. Future Microbiol. 2014;9:1165–77.
13. Webber MA, Piddock LJ. The importance of efflux pumps in bacterial antibiotic resistance. J Antimicrob Chemother. 2003;51:9–11.
14. Sharma A, Sharma R, Bhattacharyya T, Bhando T, Pathania R. Fosfomycin resistance in Acinetobacter baumannii is mediated by efflux through a major facilitator superfamily (MFS) transporter-AbaF. J Antimicrob Chemother. 2017;72:68–74.
15. Costa SS, Ntokou E, Martins A, Viveiros M, Pournaras S, Couto I, et al. Identification of the plasmid-encoded QacA efflux pump gene in meticillin-resistant Staphylococcus aureus (MRSA) strain HPV107, a representative of the MRSA iberian clone. Int J Antimicrob Agents. 2010;36:557–61.
16. Santagati M, Iannelli F, Cascone C, Campanile F, Oggioni MR, Stefani S, et al. The novel conjugative transposon TN1207.3 carries the macrolide efflux gene mef(A) in Streptococcus pyogenes. Microb Drug Resist. 2003;9:243–7.
17. Piddock LJ. Multidrug-resistance efflux pumps – Not just for resistance. Nat Rev Microbiol. 2006;4:629–36.
18. Bhardwaj AK, Mohanty P. Bacterial efflux pumps involved in multidrug resistance and their inhibitors: Rejuvinating the antimicrobial chemotherapy. Recent Pat Antiinfect Drug Discov. 2012;7:73–89.
19. Lomovskaya O, Warren MS, Lee A, Galazzo J, Fronko R, Lee M, et al. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: Novel agents for combination therapy. Antimicrob Agents Chemother. 2001;45:105–16.
20. Kothari A, Kherdekar R, Mago V, Uniyal M, Mamgain G, Kalia RB, Kumar S, Jain N, Pandey A, Omar BJ. Age of Antibiotic Resistance in MDR/XDR Clinical Pathogen of Pseudomonas aeruginosa. Pharmaceuticals. 2023 Aug 30;16(9):1230.
21. Anoushiravani M, Falsafi T, Niknam V. Proton motive force-dependent efflux of tetracycline in clinical isolates of Helicobacter pylori. J Med Microbiol. 2009;58:1309–13.
22. Fenosa A, Fusté E, Ruiz L, Veiga-Crespo P, Vinuesa T, Guallar V, et al. Role of tolC in Klebsiella oxytoca resistance to antibiotics. J Antimicrob Chemother. 2009;63:668–74.
23. Osei Sekyere J, Amoako DG. Carbonyl cyanide m-chlorophenylhydrazine (CCCP) reverses resistance to colistin, but not to carbapenems and tigecycline in multidrug-resistant Enterobacteriaceae. Front Microbiol. 2017;8:228.
24. Vargiu AV, Nikaido H. Multidrug binding properties of the AcrB efflux pump characterized by molecular dynamics simulations. Proc Natl Acad Sci. 2012;109:20637–42.
25. Gupta S, Cohen KA, Winglee K, Maiga M, Diarra B, Bishai WR. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2014;58:574–6.
26. Singh M, Jadaun GP, Ramdas, Srivastava K, Chauhan V, Mishra R, et al. Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates. Indian J Med Res. 2011;133:535–40.
27. Radchenko M, Symersky J, Nie R, Lu M. Structural basis for the blockade of MATE multidrug efflux pumps. Nat Commun. 2015;6:7995.
28. Bohnert JA, Kern WV. Selected arylpiperazines are capable of reversing multidrug resistance in Escherichia coli overexpressing RND efflux pumps. Antimicrob Agents Chemother. 2005;49:849–52.
29. Vargiu AV, Ruggerone P, Opperman TJ, Nguyen ST, Nikaido H. Molecular mechanism of MBX2319 inhibition of Escherichia coli AcrB multidrug efflux pump and comparison with other inhibitors. Antimicrob Agents Chemother. 2014;58:6224–34.
30. Stavri M, Piddock LJ, Gibbons S. Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother. 2007;59:1247–60.
31. Gibbons S, Oluwatuyi M, Kaatz GW. A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus. J Antimicrob Chemother. 2003;51:13–7.
32. Pfeifer HJ, Greenblatt DK, Koch-Wester J. Clinical toxicity of reserpine in hospitalized patients: A report from the Boston collaborative drug surveillance program. Am J Med Sci. 1976;271:269–76.
33. Kumar A, Khan IA, Koul S, Koul JL, Taneja SC, Ali I, et al. Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus. J Antimicrob Chemother. 2008;61:1270–6.
34. Sharma S, Kumar M, Sharma S, Nargotra A, Koul S, Khan IA. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother. 2010;65:1694–701.
35. Kothari A, Jain N, Kishor Kumar S, Kumar A, Kaushal K, Kaur S, Pandey A, Gaurav A, Omar BJ. Potential synergistic antibiotic combinations against fluoroquinolone-resistant Pseudomonas aeruginosa. Pharmaceuticals. 2022 Feb 18;15(2):243.
36. Fujita M, Shiota S, Kuroda T, Hatano T, Yoshida T, Mizushima T, et al. Remarkable synergies between baicalein and tetracycline, and baicalein and beta-lactams against methicillin-resistant Staphylococcus aureus. Microbiol Immunol. 2005;49:391–6.
37. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K. Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5’-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci. 2000;97:1433–7.
38. Morel C, Stermitz FR, Tegos G, Lewis K. Isoflavones as potentiators of antibacterial activity. J Agric Food Chem. 2003;51:5677–9.
39. Gibbons S, Moser E, Kaatz GW. Catechin gallates inhibit multidrug resistance (MDR) in Staphylococcus aureus. Planta Med. 2004;70:1240–2.
40. Sudano Roccaro A, Blanco AR, Giuliano F, Rusciano D, Enea V. Epigallocatechin-gallate enhances the activity of tetracycline in staphylococci by inhibiting its efflux from bacterial cells. Antimicrob Agents Chemother. 2004;48:1968–73.
41. Oluwatuyi M, Kaatz GW, Gibbons S. Antibacterial and resistance modifying activity of Rosmarinus officinalis. Phytochemistry. 2004;65:3249–54.
42. Lorenzi V, Muselli A, Bernardini AF, Berti L, Pagès JM, Amaral L, et al. Geraniol restores antibiotic activities against multidrug-resistant isolates from Gram-negative species. Antimicrob Agents Chemother. 2009;53:2209–11.
43. Opperman TJ, Nguyen ST. Recent advances toward a molecular mechanism of efflux pump inhibition. Front Microbiol. 2015;6:421.
44. Chevalier J, Atifi S, Eyraud A, Mahamoud A, Barbe J, Pagès JM. New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains. J Med Chem. 2001;44:4023–6.
45. Pradel E, Pagès JM. The AcrAB-tolC efflux pump contributes to multidrug resistance in the nosocomial pathogen Enterobacter aerogenes. Antimicrob Agents Chemother. 2002;46:2640–3.
46. Sabatini S, Gosetto F, Manfroni G, Tabarrini O, Kaatz GW, Patel D, et al. 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. 2011;54:5722–36.
47. Thorarensen A, Presley-Bodnar AL, Marotti KR, Boyle TP, Heckaman CL, Bohanon MJ, et al. 3-arylpiperidines as potentiators of existing antibacterial agents. Bioorg Med Chem Lett. 2001;11:1903–6.
48. Kaatz GW, Moudgal VV, Seo SM, Hansen JB, Kristiansen JE. Phenylpiperidine selective serotonin reuptake inhibitors interfere with multidrug efflux pump activity in Staphylococcus aureus. Int J Antimicrob Agents. 2003;22:254–61.
49. Mahmood HY, Jamshidi S, Sutton JM, Rahman KM. Current advances in developing inhibitors of bacterial multidrug efflux pumps. Curr Med Chem. 2016;23:1062–81.
50. Zechini B, Versace I. Inhibitors of multidrug resistant efflux systems in bacteria. Recent Pat Antiinfect Drug Discov. 2009;4:37–50.
51. Piddock LJ, Garvey MI, Rahman MM, Gibbons S. Natural and synthetic compounds such as trimethoprim behave as inhibitors of efflux in Gram-negative bacteria. J Antimicrob Chemother. 2010;65:1215–23.
52. Neyfakh AA, Bidnenko VE, Chen LB. Efflux-mediated multidrug resistance in Bacillus subtilis: Similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci U S A. 1991;88:4781–5.
53. Song L, Wu X. Development of efflux pump inhibitors in antituberculosis therapy. Int J Antimicrob Agents. 2016;47:421–9.
54. Fiamegos YC, Kastritis PL, Exarchou V, Han H, Bonvin AM, Vervoort J, et al. Antimicrobial and efflux pump inhibitory activity of caffeoylquinic acids from Artemisia absinthium against Gram-positive pathogenic bacteria. PLoS One. 2011;6:e18127.
55. Joshi P, Singh S, Wani A, Sharma S, Jain SK, Singh B, et al. Osthol and curcumin as inhibitors of human Pgp and multidrug efflux pumps of Staphylococcus aureus: Reversing the resistance against frontline antibacterial drugs. Med Chem Commun. 2014;5:1540–7.
56. Holler JG, Christensen SB, Slotved HC, Rasmussen HB, Gúzman A, Olsen CE, et al. Novel inhibitory activity of the Staphylococcus aureus NorA efflux pump by a kaempferol rhamnoside isolated from Persea lingue nees. J Antimicrob Chemother. 2012;67:1138–44.
57. Michalet S, Cartier G, David B, Mariotte AM, Dijoux-franca MG, Kaatz GW, et al. N-caffeoylphenalkylamide derivatives as bacterial efflux pump inhibitors. Bioorg Med Chem Lett. 2007;17:1755–8.
58. Li B, Yao Q, Pan XC, Wang N, Zhang R, Li J, et al. Artesunate enhances the antibacterial effect of {beta|-lactam antibiotics against Escherichia coli by increasing antibiotic accumulation via inhibition of the multidrug efflux pump system AcrAB-TolC. J Antimicrob Chemother. 2011;66:769–77.
59. Chérigo L, Pereda-Miranda R, Fragoso-Serrano M, Jacobo-Herrera N, Kaatz GW, Gibbons S. Inhibitors of bacterial multidrug efflux pumps from the resin glycosides of Ipomoea murucoides. J Nat Prod. 2008;71:1037–45.
60. Rana T, Singh S, Kaur N, Pathania K, Farooq U. A review on efflux pump inhibitors of medically important bacteria from plant sources. Int J Pharm Sci Rev Res. 2014;26:101–11.
61. Roy SK, Kumari N, Pahwa S, Agrahari UC, Bhutani KK, Jachak SM, et al. NorA efflux pump inhibitory activity of coumarins from Mesua ferrea. Fitoterapia. 2013;90:140–50.
62. Stermitz FR, Scriven LN, Tegos G, Lewis K. Two flavonols from Artemisa annua which potentiate the activity of berberine and norfloxacin against a resistant strain of Staphylococcus aureus. Planta Med. 2002;68:1140–1.
63. Chan BC, Ip M, Gong H, Lui SL, See RH, Jolivalt C, et al. Synergistic effects of diosmetin with erythromycin against ABC transporter over-expressed methicillin-resistant Staphylococcus aureus (MRSA) RN4220/pUL5054 and inhibition of MRSA pyruvate kinase. Phytomedicine. 2013;20:611–4.
64. Roy SK, Pahwa S, Nandanwar H, Jachak SM. Phenylpropanoids of Alpinia galangal as efflux pump inhibitors in Mycobacterium smegmatis mc2 155. Fitoterapia. 2012;83:1248–55.
65. Shiu WK, Malkinson JP, Rahman MM, Curry J, Stapleton P, Gunaratnam M, et al. A new plant-derived antibacterial is an inhibitor of efflux pumps in Staphylococcus aureus. Int J Antimicrob Agents. 2013;42:513–8.
66. Chovanová R, Mezovská J, Vaverková Š, Mikulášová M. The inhibition the Tet(K) efflux pump of tetracycline resistant Staphylococcus epidermidis by essential oils from three Salvia species. Lett Appl Microbiol. 2015;61:58–62.
67. Bruhn DF, Scherman MS, Liu J, Scherbakov D, Meibohm B, Böttger EC, et al. In vitro and in vivo evaluation of synergism between anti-tubercular spectinamides and non-classical tuberculosis antibiotics. Sci Rep. 2015;5:13985.
68. Smith EC, Williamson EM, Wareham N, Kaatz GW, Gibbons S. Antibacterials and modulators of bacterial resistance from the immature cones of Chamaecyparis lawsoniana. Phytochemistry. 2007;68:210–7.
69. Smith EC, Kaatz GW, Seo SM, Wareham N, Williamson EM, Gibbons S. The phenolic diterpene totarol inhibits multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother. 2007;51:4480–3.
70. Singh S, Kalia NP, Joshi P, Kumar A, Sharma PR, Kumar A, et al. Boeravinone B, A novel dual inhibitor of NorA bacterial efflux pump of Staphylococcus aureus and human P-glycoprotein, reduces the biofilm formation and intracellular invasion of bacteria. Front Microbiol. 2017;8:1868.
71. Limaverde PW, Campina FF, da Cunha FAB, Crispim FD, Figueredo FG, Lima LF, et al. Inhibition of the TetK efflux-pump by the essential oil of Chenopodium ambrosioides L. and α-terpinene against Staphylococcus aureus IS-58. Food Chem Toxicol. 2017;109:957–61.
72. Kakarla P, Floyd J, Mukherjee M, Devireddy AR, Inupakutika MA, Ranweera I, et al. Inhibition of the multidrug efflux pump LmrS from Staphylococcus aureus by cumin spice Cuminum cyminum. Arch Microbiol. 2017;199:465–74.
73. Fazly Bazzaz BS, Iranshahi M, Naderinasab M, Hajian S, Sabeti Z, Masumi E. Evaluation of the effects of galbanic acid from Ferula szowitsiana and conferol from F. badrakema, as modulators of multi-drug resistance in clinical isolates of Escherichia coli and Staphylococcus aureus. Res Pharm Sci. 2010;5:21–8.
74. Tintino SR, Morais-Tintino CD, Campina FF, Costa MDS, Menezes IRA, de Matos YMLS, et al. Tannic acid affects the phenotype of Staphylococcus aureus resistant to tetracycline and erythromycin by inhibition of efflux pumps. Bioorg Chem. 2017;74:197–200.
75. Siriyong T, Srimanote P, Chusri S, Yingyongnarongkul BE, Suaisom C, Tipmanee V, et al. Conessine as a novel inhibitor of multidrug efflux pump systems in Pseudomonas aeruginosa. BMC Complement Altern Med. 2017;17:405.
76. Siriyong T, Chusri S, Srimanote P, Tipmanee V, Voravuthikunchai SP. Holarrhena antidysenterica extract and its steroidal alkaloid, conessine, as resistance-modifying agents against extensively drug-resistant Acinetobacter baumannii. Microb Drug Resist. 2016;22:273–82.
77. Chan BC, Han XQ, Lui SL, Wong CW, Wang TB, Cheung DW, et al. Combating against methicillin-resistant Staphylococcus aureus – Two fatty acids from purslane (Portulaca oleracea L.) exhibit synergistic effects with erythromycin. J Pharm Pharmacol. 2015;67:107–16.
78. Falcão-Silva VS, Silva DA, Souza Mde F, Siqueira-Junior JP. Modulation of drug resistance in Staphylococcus aureus by a kaempferol glycoside from Herissantia tiubae (Malvaceae) Phytother Res. 2009;23:1367–70.
79. Kalia NP, Mahajan P, Mehra R, Nargotra A, Sharma JP, Koul S, et al. Capsaicin, a novel inhibitor of the NorA efflux pump, reduces the intracellular invasion of Staphylococcus aureus. J Antimicrob Chemother. 2012;67:2401–8.
80. Gupta VK, Tiwari N, Gupta P, Verma S, Pal A, Srivastava SK, et al. A clerodane diterpene from Polyalthia longifolia as a modifying agent of the resistance of methicillin resistant Staphylococcus aureus. Phytomedicine. 2016;23:654–61.
81. Martins A, Vasas A, Viveiros M, Molnár J, Hohmann J, Amaral L, et al. Antibacterial properties of compounds isolated from Carpobrotus edulis. Int J Antimicrob Agents. 2011;37:438–44.
82. Bharate JB, Singh S, Wani A, Sharma S, Joshi P, Khan IA, et al. Discovery of 4-acetyl-3-(4-fluorophenyl)-1-(p-tolyl)-5-methylpyrrole as a dual inhibitor of human P-glycoprotein and Staphylococcus aureus nor A efflux pump. Org Biomol Chem. 2015;13:5424–31.
83. Schindler BD, Jacinto P, Kaatz GW. Inhibition of drug efflux pumps in Staphylococcus aureus: Current status of potentiating existing antibiotics. Future Microbiol. 2013;8:491–507.
84. Holler JG, Slotved HC, Mølgaard P, Olsen CE, Christensen SB. Chalcone inhibitors of the NorA efflux pump in Staphylococcus aureus whole cells and enriched everted membrane vesicles. Bioorg Med Chem. 2012;20:4514–21.
85. Haynes KM, Abdali N, Jhawar V, Zgurskaya HI, Parks JM, Green AT, et al. Identification and structure-activity relationships of novel compounds that potentiate the activities of antibiotics in Escherichia coli. J Med Chem. 2017;60:6205–19.
86. Cortez-Cordova J, Kumar A. Activity of the efflux pump inhibitor phenylalanine-arginine β-naphthylamide against the AdeFGH pump of Acinetobacter baumannii. Int J Antimicrob Agents. 2011;37:420–4.
87. Bohnert JA, Schuster S, Kern WV, Karcz T, Olejarz A, Kaczor A, et al. 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. 2016;60:1974–83.
88. Machado D, Fernandes L, Costa SS, Cannalire R, Manfroni G, Tabarrini O, et al. Mode of action of the 2-phenylquinoline efflux inhibitor PQQ4R against Escherichia coli. Peer J. 2017;5:e3168.
89. Handzlik J, Szymańska E, Alibert S, Chevalier J, Otrębska E, Pękala E, et al. Search for new tools to combat Gram-negative resistant bacteria among amine derivatives of 5-arylidenehydantoin. Bioorg Med Chem. 2013;21:135–45.
90. Nelson ML, Levy SB. Reversal of tetracycline resistance mediated by different bacterial tetracycline resistance determinants by an inhibitor of the Tet(B) antiport protein. Antimicrob Agents Chemother. 1999;43:1719–24.
91. Tintino SR, Morais-Tintino CD, Campina FF, Pereira RL, Costa Mdo S, Braga MF, et al. Action of cholecalciferol and alpha-tocopherol on Staphylococcus aureus efflux pumps. EXCLI J. 2016;15:315–22.
92. Simons SO, Kristiansen JE, Hajos G, van der Laan T, Molnár J, Boeree MJ, et al. Activity of the efflux pump inhibitor SILA 421 against drug-resistant tuberculosis. Int J Antimicrob Agents. 2013;41:488–9.
93. Sabatini S, Kaatz GW, Rossolini GM, Brandini D, Fravolini A. From phenothiazine to 3-phenyl-1,4-benzothiazine derivatives as inhibitors of the Staphylococcus aureus NorA multidrug efflux pump. J Med Chem. 2008;51:4321–30.
94. Song Y, Qin R, Pan X, Ouyang Q, Liu T, Zhai Z, et al. Design of new antibacterial enhancers based on AcrB's structure and the evaluation of their antibacterial enhancement activity. Int J Mol Sci. 2016;17 pii: E1934.
95. Costa LM, de Macedo EV, Oliveira FA, Ferreira JH, Gutierrez SJ, Peláez WJ, et al. Inhibition of the NorA efflux pump of Staphylococcus aureus by synthetic riparins. J Appl Microbiol. 2016;121:1312–22.
96. Coêlho ML, Ferreira JH, de Siqueira Júnior JP, Kaatz GW, Barreto HM, de Carvalho Melo Cavalcante AA, et al. Inhibition of the NorA multi-drug transporter by oxygenated monoterpenes. Microb Pathog. 2016;99:173–7.
97. Wani NA, Singh S, Farooq S, Shankar S, Koul S, Khan IA, et al. Amino acid amides of piperic acid (PA) and 4-ethylpiperic acid (EPA) as NorA efflux pump inhibitors of Staphylococcus aureus. Bioorg Med Chem Lett. 2016;26:4174–8.
98. Fontaine F, Héquet A, Voisin-Chiret AS, Bouillon A, Lesnard A, Cresteil T, et al. Boronic species as promising inhibitors of the Staphylococcus aureus NorA efflux pump: Study of 6-substituted pyridine-3-boronic acid derivatives. Eur J Med Chem. 2015;95:185–98.
99. Zhang J, Sun Y, Wang Y, Lu M, He J, Liu J, et al. Non-antibiotic agent ginsenoside 20(S)-rh2 enhanced the antibacterial effects of ciprofloxacin in vitro and in vivo as a potential NorA inhibitor. Eur J Pharmacol. 2014;740:277–84.
100. Bohnert JA, Schuster S, Kern WV. Pimozide inhibits the AcrAB-tolC efflux pump in Escherichia coli. Open Microbiol J. 2013;7:83–6.
101. Lee MD, Galazzo JL, Staley AL, Lee JC, Warren MS, Fuernkranz H, et al. Microbial fermentation-derived inhibitors of efflux-pump-mediated drug resistance. Farmaco. 2001;56:81–5.
102. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic – A vision for applied use. Biochem Pharmacol. 2006;71:910–8.
103. Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, et al. Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA. 2013;310:2544–53.
104. Nakajima A, Sugimoto Y, Yoneyama H, Nakae T. High-level fluoroquinolone resistance in Pseudomonas aeruginosa due to interplay of the MexAB-oprM efflux pump and the DNA gyrase mutation. Microbiol Immunol. 2002;46:391–5
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Aug 16, 2023
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Ankur Kumar, Ganesh Kumar Verma, Avinash Bairwa, Priyanka Singh, Jitender Gairolla, Bhawna Lakhawat, Priyanka Naithani, Ashish Kothari, & Balram Ji Omar. (2023). EFFLUX PUMP INHIBITORS: PAVING THE WAY FROM RESEARCH BENCH TO BEDSIDE BATTLE AGAINST BACTERIAL PATHOGENS. Journal of Population Therapeutics and Clinical Pharmacology, 30(16), 905–916. https://doi.org/10.53555/jptcp.v30i16.4846
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Author Biographies
Ankur Kumar
Department of Microbiology, All India Institute of Medical Sciences, Rishikesh-249203
Ganesh Kumar Verma
Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh-249203
Avinash Bairwa
Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh-249203
Priyanka Singh
Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore-632014
Jitender Gairolla
Department of Microbiology, All India Institute of Medical Sciences, Rishikesh-249203
Bhawna Lakhawat
Department of Pharmacology, All India Institute of Medical Sciences, Bhubaneswar-751019
Priyanka Naithani
Center of excellence for control of Zoonoses under National One Health Programme, AIIMS, Rishikesh-2492036
Ashish Kothari
Department of Microbiology, All India Institute of Medical Sciences, Rishikesh-249203
Balram Ji Omar
Professor Department of Microbiology, All India Institute of Medical Sciences, Rishikesh-249203