Efflux pump inhibitors: Targeting mycobacterial efflux systems to enhance TB therapy

Journal of Antimicrobial Chemotherapy

Volumn 71, Issue 1, 2016, Pages 17-26

  Pule, Caroline M ^a   Sampson, Samantha L ^a   Warren, Robin M ^a   Black, Philippa A ^a   van Helden, Paul D ^a   Victor, Tommie C ^a   Louw, Gail E ^a  

^a UNIVERSITY OF STELLENBOSCH   (South Africa)

Author keywords

[No Author keywords available]

Indexed keywords

BERBERINE; CALCIUM CHANNEL BLOCKING AGENT; EFFLUX PUMP INHIBITOR; PHENOTHIAZINE DERIVATIVE; PIPERINE; PROTONOPHORE; RESERPINE; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG; VALINOMYCIN; VERAPAMIL; BEDAQUILINE; CARRIER PROTEIN; CLOFAZIMINE; QUINOLINE DERIVATIVE;

ADJUVANT THERAPY; ANTIBIOTIC THERAPY; ARTICLE; BACTERIAL GROWTH; DRUG ACTIVITY; DRUG EFFICACY; DRUG TARGETING; HUMAN; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; ACTIVE TRANSPORT; ANTIBIOTIC RESISTANCE; DRUG EFFECTS; METABOLISM;

ANTITUBERCULAR AGENTS; BIOLOGICAL TRANSPORT, ACTIVE; CLOFAZIMINE; DIARYLQUINOLINES; DRUG RESISTANCE, BACTERIAL; HUMANS; MEMBRANE TRANSPORT PROTEINS; MYCOBACTERIUM TUBERCULOSIS;

EID: 84960078594     PISSN: 03057453     EISSN: 14602091     Source Type: Journal    
DOI: 10.1093/jac/dkv316     Document Type: Article

References (92)

1. Andries K, Villellas C, Coeck N et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLoS One 2014; 9: e102135.
2. Nagabushan H, Roopadevi HS. Bedaquiline: a novel antitubercular drug for multidrug-resistant tuberculosis. J Postgrad Med 2014; 60: 300-2.
3. Gupta S, Cohen KA, Winglee K et al. Efflux inhibition with verapamil potentiates bedaquiline in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014; 58: 574-6.
4. Andries K, Verhasselt P, Guillemont J et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 2005; 307: 223-7.
5. Diacon AH, Pym A, Grobusch M et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009; 360: 2397-405.
6. Koul A, Vranckx L, Dendouga N et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J Biol Chem 2008; 283: 25273-80.
7. Diacon AH, Pym A, Grobusch MP et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. N Engl J Med 2014; 371: 723-32.
8. Williams K, Minkowski A, Amoabeng O et al. Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother 2012; 56: 3114-20.
9. Louw GE, Warren RM, van Pittius NCG et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. Am J Respir Crit Care Med 2011; 184: 269-76.
10. Piddock LJ, Ricci V. Accumulation of KRM-1648 by Mycobacterium aurum and Mycobacterium tuberculosis. J Antimicrob Chemother 2000; 45: 681-4.
11. Piddock LJV, Williams KJ, Ricci V. Accumulation of rifampicin by Mycobacterium aurum, Mycobacterium smegmatis and Mycobacterium tuberculosis. J Antimicrob Chemother 2000; 45: 159-65.
12. Williams KJ, Chung GAC, Piddock LJV. Accumulation of norfloxacin by Mycobacterium aurum and Mycobacterium smegmatis. Antimicrob Agents Chemother 1998; 42: 795-800.
13. Corti S, Chevalier J, Cremieux A. Intracellular accumulation of norfloxacin in Mycobacterium smegmatis. Antimicrob Agents Chemother 1995; 39: 2466-71.
14. Adams KN, Takaki K, Connolly LE et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 2011; 145: 39-53.
15. Adams KN, Szumowski JD, Ramakrishnan L. Verapamil, and its metabolite norverapamil, inhibit macrophage-induced, bacterial efflux pumpmediated tolerance to multiple anti-tubercular drugs. J Infect Dis 2014; 210: 456-66.
16. Schmalstieg AM, Srivastava S, Belkaya S et al. The antibiotic resistance arrow of time: efflux pump induction is a general first step in the evolution of mycobacterial drug resistance. Antimicrob Agents Chemother 2012; 56: 4806-15.
17. Machado D, Couto I, Perdigão J et al. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS One 2012; 7: e34538.
18. Li X-Z, Nikaido H. Efflux-mediated drug resistance in bacteria. Drugs 2004; 64: 159-204.
19. De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol Rev 2006; 30: 36-52.
20. Paulsen IT, Brown MH, Skurray RA. Proton-dependent multidrug efflux systems. Microbiol Rev 1996; 60: 575-608.
21. Balganesh M, Dinesh N, Sharma S et al. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates. Antimicrob Agents Chemother 2012; 56: 2643-51.
22. Pos KM. Drug transport mechanism of the AcrB efflux pump. Biochim Biophys Acta 2009; 1794: 782-93.
23. Seeger MA, Diederichs K, Eicher Tet al. The AcrB efflux pump: conformational cycling and peristalsis lead to multidrug resistance. Curr Drug Targets 2008; 9: 729-49.
24. Martins A, Spengler G, Rodrigues L et al. pH modulation of efflux pump activity of multi-drug resistant Escherichia coli: protection during its passage and eventual colonization of the colon. PLoS One 2009; 4: e6656.
25. Amaral L, Martins A, Spengler G et al. Efflux pumps of Gram-negative bacteria: what they do, how they do it, with what and how to deal with them. Front Pharmacol 2014; 4: 168.
26. Amaral L, Fanning S, Pages JM. Efflux pumps of Gram-negative bacteria: genetic responses to stress and the modulation of their activity by pH, inhibitors, and phenothiazines. Adv Enzymol Relat Areas Mol Biol 2011; 77: 61-108.
27. Viveiros M, Martins M, Rodrigues L et al. Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs. Expert Rev Anti Infect Ther 2012; 10: 983-98.
28. Ramón-García S, Martín C, Aínsa JA et al. Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum. J Antimicrob Chemother 2006; 57: 252-9.
29. Pasca MR, Guglierame P, Arcesi F. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2004; 48: 3175-8.
30. Rodrigues L, Aínsa JA, Amaral L et al. Inhibition of drug efflux in mycobacteria with phenothiazines and other putative efflux inhibitors. Recent Pat Antiinfect Drug Discov 2011; 6: 118-27.
31. Rodrigues L, Sampaio D, Couto I et al. The role of efflux pumps in macrolide resistance in Mycobacterium avium complex. Int J Antimicrob Agents 2009; 34: 529-33.
32. Singh M, Jadaun GPS, Ramdas et al. Effect of efflux pump inhibitors on drug susceptibility of ofloxacin resistant Mycobacterium tuberculosis isolates. Indian J Med Res 2011; 133: 535-40.
33. Banerjee SK, Bhatt K, Rana S et al. Involvement of an efflux system in mediating high level of fluoroquinolone resistance in Mycobacterium smegmatis. Biochem Biophys Res Commun 1996; 226: 362-8.
34. Mahamoud A, Chevalier J, Alibert-Franco S et al. Antibiotic efflux pumps in Gram-negative bacteria: the inhibitor response strategy. J Antimicrob Chemother 2007; 59: 1223-9.
35. Andersen CL, Holland IB, Jacq A. Verapamil, a Ca2+ channel inhibitor acts as a local anesthetic and induces the sigma E dependent extracytoplasmic stress response in E. coli. Biochim Biophys Acta 2006; 1758: 1587-95.
36. Beck E, Sieber WJ, Trejo R. Management of cluster headache. Am Fam Physician 2005; 71: 717-24.
37. McTavish D, Sorkin EM. Verapamil. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs 1989; 38: 19-76.
38. Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem 1989; 58: 137-71.
39. Poelarends GJ, Mazurkiewicz P, Konings WN. Multidrug transporters and antibiotic resistance in Lactococcus lactis. Biochim Biophys Acta 2002; 1555: 1-7.
40. Rodrigues L, Machado D, Couto I et al. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect Genet Evol 2012; 12: 695-700.
41. Gupta S, Tyagi S, Almeida DV et al. Acceleration of tuberculosis treatment by adjunctive therapy with verapamil as an efflux inhibitor. Am J Respir Crit Care Med 2013; 188: 600-7.
42. Rodrigues L, Villellas C, Bailo R et al. Role of the Mmrefflux pump in drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2013; 57: 751-7.
43. Sun Z, Xu Y, Sun Y et al. Ofloxacin resistance in Mycobacterium tuberculosis is associated with efflux pump activity independent of resistance pattern and genotype. Microb Drug Resist 2014; 20: 525-32.
44. Gupta AK, Chauhan DS, Srivastava K et al. Estimation of efflux mediated multi-drug resistance and its correlation with expression levels of two major efflux pumps in mycobacteria. J Commun Dis 2006; 38: 246-54.
45. Singh K, Kumar M, Pavadai E et al. Synthesis of new verapamil analogues and their evaluation in combination with rifampicin against Mycobacterium tuberculosis and molecular docking studies in the binding site of efflux protein Rv1258c. Bioorg Med Chem Lett 2014; 24: 2985-90.
46. National Center for Biotechnology Information. Phenothiazine. PubChem Compound Database; CID 1/4 7108. http://pubchem.ncbi.nlm.nih. gov/compound/7108.
47. Ordway D, Viveiros M, Leandro C et al. Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 917-22.
48. Amaral L, Kristiansen JE, Abebe LS et al. Inhibition of the respiration of multi-drug resistant clinical isolates of Mycobacterium tuberculosis by thioridazine: potential use for initial therapy of freshly diagnosed tuberculosis. J Antimicrob Chemother 1996; 38: 1049-53.
49. Viveiros M, Amaral L. Enhancement of antibiotic activity against polydrug resistant Mycobacterium tuberculosis by phenothiazines. Int J Antimicrob Agents 2001; 17: 225-8.
50. Molná r J, Hevér A, Fakla I et al. Inhibition of the transport function of membrane proteins bysome substituted phenothiazines in E. coli and multidrug resistant tumor cells. Anticancer Res 1997; 17: 481-6.
51. Amaral L, Martins M, Viveiros M. Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J Antimicrob Chemother 2007; 59: 1237-46.
52. Rodrigues L,Wagner D, Viveiros M et al. Thioridazine and chlorpromazine inhibition of ethidium bromide efflux in Mycobacterium avium and Mycobacterium smegmatis. J Antimicrob Chemother 2008; 61: 1076-82.
53. Martins M, Viveiros M, Amaral L. Inhibitors of Ca2+ and K+ transport enhance intracellular killing of M. tuberculosis by non-killing macrophages. In Vivo 2008; 22: 69-75.
54. Martins M, Schelz Z, Martins A et al. In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis. Int J Antimicrob Agents 2007; 29: 338-40.
55. Van Bambeke F, Page's J-M, Lee VJ. Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent Pat Antiinfect Drug Discov 2006; 1: 157-75.
56. Park JW, Lee SY, Yang JY et al. Effect of carbonyl cyanide m-chlorophenylhydrazone (CCCP) on the dimerization of lipoprotein lipase. Biochim Biophys Acta 1997; 1344: 132-8.
57. Gupta AK, Reddy VP, Lavania M et al. jefA (Rv2459), a drug efflux gene in Mycobacterium tuberculosis confers resistance to isoniazid & ethambutol. Indian J Med Res 2010; 132: 176-88.
58. Ramón-García S, Martín C, Thompson CJ et al. Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob Agents Chemother 2009; 53: 3675-82.
59. Silva PE, Bigi F, Santangelo MP et al. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob Agents Chemother 2001; 45: 800-4.
60. Milano A, Pasca MR, Provvedi R et al. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system. Tuberculosis (Edinb) 2009; 89: 84-90.
61. Rose L, Jenkins ATA. The effect of the ionophore valinomycin on biomimetic solid supported lipid DPPTE/EPC membranes. Bioelectrochemistry 2007; 70: 387-93.
62. Daniele RP, Holian SK. A potassium ionophore (valinomycin) inhibits lymphocyte proliferation by its effects on the cell membrane. Proc Natl Acad Sci USA 1976; 73: 3599-602.
63. Zhang Y, Scorpio A, Nikaido H et al. Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J Bacteriol 1999; 181: 2044-9.
64. Choudhuri BS, Sen S, Chakrabarti P. Isoniazid accumulation in Mycobacterium smegmatis is modulated by proton motive force-driven and ATP-dependent extrusion systems. Biochem Biophys Res Commun 1999; 256: 682-4.
65. Stavri M, Piddock LJV, Gibbons S. Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 2007; 59: 1247-60.
66. Plummer AJ, Earl A, Schneider JA et al. Pharmacology of Rauwolfia alkaloids, including reserpine. Ann N Y Acad Sci 1954; 59: 8-21.
67. Khan IA, Mirza ZM, Kumar A et al. Piperine, a phytochemical potentiator of ciprofloxacin against Staphylococcus aureus. Antimicrob Agents Chemother 2006; 50: 810-2.
68. Atal CK, Dubey RK, Singh J. Biochemical basis of enhanced drug bioavailability by piperine: evidence that piperine is a potent inhibitor of drug metabolism. J Pharmacol Exp Ther 1985; 232: 258-62.
69. Iwu MM, Court WE. Root alkaloids of Rauwolfia vomitoria Afz. Planta Med 1977; 32: 88-99.
70. Gibbons S, Udo EE. The effect of reserpine, a modulator of multidrug efflux pumps, on the in vitro activity of tetracycline against clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) possessing the tet(K) determinant. Phytother Res 2000; 14: 139-40.
71. Klyachko KA, Schuldiner S, Neyfakh AA. Mutations affecting substrate specificity of the Bacillus subtilis multidrug transporter Bmr. J Bacteriol 1997; 179: 2189-93.
72. Neyfakh AA, Bidnenko VE, Chen LB. Efflux-mediated multidrug resistance in Bacillus subtilis: similarities and dissimilarities with the mammalian system. Proc Natl Acad Sci USA 1991; 88: 4781-5.
73. Pasca MR, Guglierame P, De Rossi E et al. mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob Agents Chemother 2005; 49: 4775-7.
74. Colangeli R, Helb D, Sridharan S et al. The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drugtolerance to both isoniazid and ethambutol. Mol Microbiol 2005; 55: 1829-40.
75. Viveiros M, Portugal I, Bettencourt R et al. Isoniazid-induced transient high-level resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother 2002; 46: 2804-10.
76. Zhang Y, Permar S, Sun Z. Conditions that may affect the results of susceptibility testing of Mycobacterium tuberculosis to pyrazinamide. J Med Microbiol 2002; 51: 42-9.
77. Bhardwaj RK, Glaeser H, Becquemont L et al. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. harmacol Exp Ther 2002; 302: 645-50.
78. Singh J, Dubey RK, Atal CK. Piperine-mediated inhibition of glucuronidation activity in isolated epithelial cells of the guinea-pig small intestine: evidence that piperine lowers the endogeneous UDP-glucuronic acid content. J Pharmacol Exp Ther 1986; 236: 488-93.
79. Sharma S, Kumar M, Sharma S et al. Piperine as an inhibitor of Rv1258c, a putative multidrug efflux pump of Mycobacterium tuberculosis. J Antimicrob Chemother 2010; 65: 1694-701.
80. Jin J, Zhang J, Guo N et al. The plant alkaloid piperine as a potential inhibitor of ethidium bromide efflux in Mycobacterium smegmatis. J Med Microbiol 2011; 60: 223-9.
81. Sharma S, Kalia NP, Suden P et al. Protective efficacy of piperine against Mycobacterium tuberculosis. Tuberculosis (Edinb) 2014; 94: 389-96.
82. Thota N, Koul S, Reddy MV et al. Citral derived amides as potent bacterial NorA efflux pump inhibitors. Bioorg Med Chem 2008; 16: 6535-43.
83. Bhadra K, Kumar GS. Therapeutic potential of nucleic acid-binding isoquinoline alkaloids: binding aspects and implications for drug design. Med Res Rev 2011; 31: 821-62.
84. Kuo C-L, Chi C-W, Liu T-Y. The anti-inflammatory potential of berberine in vitro and in vivo. Cancer Lett 2004; 203: 127-37.
85. Kim JB, Yu J-H, Ko E et al. The alkaloid berberine inhibits the growth of anoikis-resistant MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell cycle arrest. Phytomedicine 2010; 17: 436-40.
86. Stermitz FR, Lorenz P, Tawara JN et al. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA 2000; 97: 1433-7.
87. Markham PN, Westhaus E, Klyachko K et al. Multiple novel inhibitors of the NorA multidrug transporter of Staphylococcus aureus. Antimicrob Agents Chemother 1999; 43: 2404-8.
88. Yamasaki S, Nikaido E, Nakashima R et al. The crystal structure of multidrug-resistance regulator RamR with multiple drugs. Nat Commun 2013; 4: 2078.
89. Szumowski JD, Adams KN, Edelstein PH et al. Antimicrobial efflux pumps and Mycobacterium tuberculosis drug tolerance: evolutionary considerations. Curr Top Microbiol Immunol 2013; 374: 81-108.
90. Johnston A, Burgess CD, Hamer J. Systemic availability of oral verapamil and effect on PR interval in man. Br J Clin Pharmacol 1981; 12: 397-400.
91. Jin J, Zhang J-Y, Guo N et al. Farnesol, a potential efflux pump inhibitor in Mycobacterium smegmatis. Mol Basel Switz 2010; 15: 7750-62.
92. Grossman TH, Shoen CM, Jones SM et al. The efflux pump inhibitor timcodar improves the potency of antimycobacterial agents. Antimicrob Agents Chemother 2015; 59: 1534-41.