Inhibitors of mycobacterial efflux pumps as potential boosters for anti-tubercular drugs

Expert Review of Anti-Infective Therapy

Volumn 10, Issue 9, 2012, Pages 983-998

  Viveiros, Miguel ^a,b   Martins, Marta ^b,c   Rodrigues, Liliana ^b,d,e   Machado, Diana ^a   Couto, Isabel ^a,f   Ainsa, José ^b,d,f   Amaral, Leonard ^a,b  

^a UNIVERSIDADE NOVA DE LISBOA   (Portugal)

^b EUROPEAN COMMISSION   (Belgium)

^c UNIVERSITY COLLEGE DUBLIN   (Ireland)

^d UNIVERSITY OF ZARAGOZA   (Spain)

^e INSTITUTO DE SALUD CARLOS III   (Spain)

^f UNIVERSIDADE NOVA DE LISBOA   (Portugal)

Author keywords

drug resistance; efflux pump inhibitors; efflux pumps; macrophage killing activity; multidrug resistant tuberculosis; mycobacteria; phenothiazines; tuberculosis

Indexed keywords

ACRIDINE; ACRIFLAVINE; BETA LACTAM ANTIBIOTIC; BROMPERIDOL; BUTYROPHENONE DERIVATIVE; CARBONYL CYANIDE CHLOROPHENYLHYDRAZONE; CARRIER PROTEIN; CHLORAMPHENICOL; CHLORPROMAZINE; CIPROFLOXACIN; DOXORUBICIN; ETHAMBUTOL; ETHIDIUM BROMIDE; FARNESOL; FLUPENTIXOL; HALOPERIDOL; IPRONIAZID; ISONIAZID; NORFLOXACIN; PHENOTHIAZINE DERIVATIVE; PHENYLALKYLAMINE; RESERPINE; STREPTOMYCIN; TETRACYCLINE; THIORIDAZINE; THIOXANTHENE; TUBERCULOSTATIC AGENT; UNINDEXED DRUG; VERAPAMIL;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; BACTERIAL CELL WALL; CELL MEMBRANE PERMEABILITY; DRUG POTENTIATION; DRUG STRUCTURE; DRUG TRANSPORT; EFFLUX PUMP; HUMAN; LUNG TUBERCULOSIS; MACROPHAGE; MYCOBACTERIUM; NONHUMAN; REVIEW; TUBERCULOSIS;

ANTITUBERCULAR AGENTS; BACTERIAL PROTEINS; BIOLOGICAL TRANSPORT; DRUG RESISTANCE, BACTERIAL; DRUG SYNERGISM; DRUG THERAPY, COMBINATION; HUMANS; MEMBRANE TRANSPORT PROTEINS; MODELS, BIOLOGICAL; MYCOBACTERIUM TUBERCULOSIS; TUBERCULOSIS, MULTIDRUG-RESISTANT;

EID: 84868155091     PISSN: 14787210     EISSN: 17448336     Source Type: Journal    
DOI: 10.1586/eri.12.89     Document Type: Review

References (128)

1. WHO. Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Press, Geneva, Switzerland (2011).
2. Viveiros M, Leandro C, Amaral L. Mycobacterial efflux pumps and chemotherapeutic implications. Int. J. Antimicrob. Agents 22(3), 274-278 (2003).
3. da Silva PE, Von Groll A, Martin A, Palomino JC. Efflux as a mechanism for drug resistance in Mycobacterium tuberculosis. FEMS Immunol. Med. Microbiol. 63(1), 1-9 (2011).
4. Pasipanodya JG, Gumbo T. A new evolutionary and pharmacokineticYpharmacodynamic scenario for rapid emergence of resistance to single and multiple anti-tuberculosis drugs. Curr. Opin. Pharmacol. 11(5), 457-463 (2011).
5. Wayne LG. Dormancy of Mycobacterium tuberculosis and latency of disease. Eur. J. Clin. Microbiol. Infect. Dis. 13(11), 908-914 (1994).
6. Elliott AM, Berning SE, Iseman MD, Peloquin CA. Failure of drug penetration and acquisition of drug resistance in chronic tuberculous empyema. Tuber. Lung Dis. 76(5), 463-467 (1995).
7. WHO. Extensively drug-resistant tuberculosis (XDRTB): recommendations for prevention and control. Weekly Epidemiol. Record. 81, 430-432 (2006).
8. Brudney K, Dobkin J. Resurgent tuberculosis in New York City. Human immunodeficiency virus, homelessness, and the decline of tuberculosis control programs. Am. Rev. Respir. Dis. 144(4), 745-749 (1991).
9. Daniel TM. The history of tuberculosis. Respir. Med. 100(11), 1862-1870 (2006).
10. Stop TB Partnership. In: The Global Plan to Stop TB, 2006-2015: actions for life: towards a world free of tuberculosis. WHO Press, Geneva, Switzerland (2006).
11. Migliori GB, Loddenkemper R, Blasi F, Raviglione MC. 125 years after Robert Koch's discovery of the tubercle bacillus: the new XDR-TB threat. Is "science" enough to tackle the epidemic? Eur. Respir. J. 29(3), 423-427 (2007).
12. Migliori GB, Ortmann J, Girardi E et al. SMIRA/TBNET Study Group. Extensively drug-resistant tuberculosis, Italy and Germany. Emerging Infect. Dis. 13(5), 780-782 (2007).
13. Velayati AA, Masjedi MR, Farnia P et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 136(2), 420-425 (2009).
14. Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin. Infect. Dis. 54(4), 579-581 (2012).
15. Jarlier V, Nikaido H. Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol. Lett. 123(1-2), 11-18 (1994).
16. Nguyen L, Thompson CJ. Foundations of antibiotic resistance in bacterial physiology: the mycobacterial paradigm. Trends Microbiol. 14(7), 304-312 (2006).
17. Louw GE, Warren RM, Gey van Pittius NC, McEvoy CR, Van Helden PD, Victor TC. A balancing act: efflux/influx in mycobacterial drug resistance. Antimicrob. Agents Chemother. 53(8), 3181-3189 (2009).
18. Machado D, Couto I, Perdigão J et al. Contribution of efflux to the emergence of isoniazid and multidrug resistance in Mycobacterium tuberculosis. PLoS ONE 7(4), e34538 (2012).
19. de Steenwinkel JE, de Knegt GJ, ten Kate MT et al. Time-kill kinetics of antituberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis. J. Antimicrob. Chemother. 65(12), 2582-2589 (2010).
20. Srivastava S, Musuka S, Sherman C, Meek C, Leff R, Gumbo T. Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol. J. Infect. Dis. 201(8), 1225-1231 (2010).
21. Quinn T, O'Mahony R, Baird AW, Drudy D, Whyte P, Fanning S. Multi-drug resistance in Salmonella enterica: efflux mechanisms and their relationships with the development of chromosomal resistance gene clusters. Curr. Drug Targets 7(7), 849-860 (2006).
22. Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin. Microbiol. Rev. 19(2), 382-402 (2006).
23. Nikaido H, Pagès JM. Broad-specificity efflux pumps and their role in multidrug resistance of Gram-negative bacteria. FEMS Microbiol. Rev. 36(2), 340-363 (2012).
24. Niederweis M, Danilchanka O, Huff J, Hoffmann C, Engelhardt H. Mycobacterial outer membranes: in search of proteins. Trends Microbiol. 18(3), 109-116 (2010).
25. Niederweis M. Mycobacterial porins Y new channel proteins in unique outer membranes. Mol. Microbiol. 49(5), 1167-1177 (2003).
26. Siroy A, Mailaender C, Harder D et al. Rv1698 of Mycobacterium tuberculosis represents a new class of channel-forming outer membrane proteins. J. Biol. Chem. 283(26), 17827-17837 (2008).
27. Mailaender C, Reiling N, Engelhardt H, Bossmann S, Ehlers S, Niederweis M. The MspA porin promotes growth and increases antibiotic susceptibility of both Mycobacterium bovis BCG and Mycobacterium tuberculosis. Microbiology (Reading, Engl.) 150(Pt 4), 853-864 (2004).
28. Nikaido H. Preventing drug access to targets: cell surface permeability barriers and active efflux in bacteria. Semin. Cell Dev. Biol. 12(3), 215-223 (2001).
29. Aínsa JA, Blokpoel MC, Otal I, Young DB, De Smet KA, Martín C. Molecular cloning and characterization of Tap, a putative multidrug efflux pump present in Mycobacterium fortuitum and Mycobacterium tuberculosis. J. Bacteriol. 180(22), 5836-5843 (1998).
30. De Rossi E, Blokpoel MC, Cantoni R et al. Molecular cloning and functional analysis of a novel tetracycline resistance determinant, Tet(V), from Mycobacterium smegmatis. Antimicrob. Agents Chemother. 42(8), 1931-1937 (1998).
31. Li XZ, Zhang L, Nikaido H. Efflux pump-mediated intrinsic drug resistance in Mycobacterium smegmatis. Antimicrob. Agents Chemother. 48(7), 2415-2423 (2004).
32. Pasca MR, Guglierame P, De Rossi E, Zara F, Riccardi G. mmpL7 gene of Mycobacterium tuberculosis is responsible for isoniazid efflux in Mycobacterium smegmatis. Antimicrob. Agents Chemother. 49(11), 4775-4777 (2005).
33. Silva PE, Bigi F, Santangelo MP et al. Characterization of P55, a multidrug efflux pump in Mycobacterium bovis and Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 45(3), 800-804 (2001).
34. Viveiros M, Portugal I, Bettencourt R et al. Isoniazid-induced transient high-level resistance in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 46(9), 2804-2810 (2002).
35. Colangeli R, Helb D, Sridharan S et al. The Mycobacterium tuberculosis iniA gene is essential for activity of an efflux pump that confers drug tolerance to both isoniazid and ethambutol. Mol. Microbiol. 55(6), 1829-1840 (2005).
36. Ramón-García S, Martín C, Thompson CJ, Aínsa JA. Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth. Antimicrob. Agents Chemother. 53(9), 3675-3682 (2009).
37. De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol. Rev. 30(1), 36-52 (2006).
38. Liu J, Takiff HE, Nikaido H. Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. J. Bacteriol. 178(13), 3791-3795 (1996).
39. Sander P, De Rossi E, Böddinghaus B et al. Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance. FEMS Microbiol. Lett. 193(1), 19-23 (2000).
40. Takiff HE, Cimino M, Musso MC et al. Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc. Natl Acad. Sci. USA 93(1), 362-366 (1996).
41. Buroni S, Manina G, Guglierame P, Pasca MR, Riccardi G, De Rossi E. LfrR is a repressor that regulates expression of the efflux pump LfrA in Mycobacterium smegmatis. Antimicrob. Agents Chemother. 50(12), 4044-4052 (2006).
42. De Rossi E, Arrigo P, Bellinzoni M et al. The multidrug transporters belonging to major facilitator superfamily in Mycobacterium tuberculosis. Mol. Med. 8(11), 714-724 (2002).
43. Siddiqi N, Das R, Pathak N et al. Mycobacterium tuberculosis isolate with a distinct genomic identity overexpresses a Tap-like efflux pump. Infection 32(2), 109-111 (2004).
44. Ramón-García S, Martín C, Aínsa JA, De Rossi E. Characterization of tetracycline resistance mediated by the efflux pump Tap from Mycobacterium fortuitum. J. Antimicrob. Chemother. 57(2), 252-259 (2006).
45. Ramón-García S, Mick V, Dainese E et al. Functional and genetic characterization of the Tap efflux pump in Mycobacterium bovis BCG. Antimicrob. Agents Chemother. 56(4), 2074-2083 (2012).
46. Adams KN, Takaki K, Connolly LE et al. Drug tolerance in replicating mycobacteria mediated by a macrophageinduced efflux mechanism. Cell 145(1), 39-53 (2011).
47. Bianco MV, Blanco FC, Imperiale B et al. Role of p27Yp55 operon from Mycobacterium tuberculosis in the resistance to toxic compounds. BMC Infect. Dis. 11, 195 (2011).
48. Farrow MF, Rubin EJ. Function of a mycobacterial major facilitator superfamily pump requires a membrane-associated lipoprotein. J. Bacteriol. 190(5), 1783-1791 (2008).
49. Bianco MV, Blanco FC, Forrellad MA et al. Knockout mutation of p27-p55 operon severely reduces replication of Mycobacterium bovis in a macrophagic cell line and survival in a mouse model of infection. Virulence 2(3), 233-237 (2011).
50. Doran JL, Pang Y, Mdluli KE et al. Mycobacterium tuberculosis efpA encodes an efflux protein of the QacA transporter family. Clin. Diagn. Lab. Immunol. 4(1), 23-32 (1997).
51. Wilson M, DeRisi J, Kristensen HH et al. Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. Proc. Natl Acad. Sci. USA 96(22), 12833-12838 (1999).
52. Zhang M, Yue J, Yang YP et al. Detection of mutations associated with isoniazid resistance in Mycobacterium tuberculosis isolates from China. J. Clin. Microbiol. 43(11), 5477-5482 (2005).
53. Ramón-García S, Martín C, De Rossi E, Aínsa JA. Contribution of the Rv2333c efflux pump (the Stp protein) from Mycobacterium tuberculosis to intrinsic antibiotic resistance in Mycobacterium bovis BCG. J. Antimicrob. Chemother. 59(3), 544-547 (2007).
54. Tekaia F, Gordon SV, Garnier T, Brosch R, Barrell BG, Cole ST. Analysis of the proteome of Mycobacterium tuberculosis in silico. Tuber. Lung Dis. 79(6), 329-342 (1999).
55. Domenech P, Reed MB, Barry CE 3rd. Contribution of the Mycobacterium tuberculosis MmpL protein family to virulence and drug resistance. Infect. Immun. 73(6), 3492-3501 (2005).
56. Camacho LR, Constant P, Raynaud C et al. Analysis of the phthiocerol dimycocerosate locus of Mycobacterium tuberculosis. Evidence that this lipid is involved in the cell wall permeability barrier. J. Biol. Chem. 276(23), 19845-19854 (2001).
57. Rodrigues L, Machado D, Couto I, Amaral L, Viveiros M. Contribution of efflux activity to isoniazid resistance in the Mycobacterium tuberculosis complex. Infect. Genet. Evol. 12(4), 695-700 (2012).
58. Milano A, Pasca MR, Provvedi R et al. Azole resistance in Mycobacterium tuberculosis is mediated by the MmpS5-MmpL5 efflux system. Tuberculosis (Edinb). 89(1), 84-90 (2009).
59. De Rossi E, Branzoni M, Cantoni R, Milano A, Riccardi G, Ciferri O. mmr, a Mycobacterium tuberculosis gene conferring resistance to small cationic dyes and inhibitors. J. Bacteriol. 180(22), 6068-6071 (1998).
60. Gupta AK, Katoch VM, Chauhan DS et al. Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microb. Drug Resist. 16(1), 21-28 (2010).
61. Balganesh M, Dinesh N, Sharma S, Kuruppath S, Nair AV, Sharma U. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates. Antimicrob. Agents Chemother. 56(5), 2643-2651 (2012).
62. Alland D, Kramnik I, Weisbrod TR et al. Identification of differentially expressed mRNA in prokaryotic organisms by customized amplification libraries (DECAL): the effect of isoniazid on gene expression in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 95(22), 13227-13232 (1998).
63. Braibant M, Gilot P, Content J. The ATP binding cassette (ABC) transport systems of Mycobacterium tuberculosis. FEMS Microbiol. Rev. 24(4), 449-467 (2000).
64. Choudhuri BS, Bhakta S, Barik R, Basu J, Kundu M, Chakrabarti P. Overexpression and functional characterization of an ABC (ATP-binding cassette) transporter encoded by the genes drrA and drrB of Mycobacterium tuberculosis. Biochem. J. 367(Pt 1), 279-285 (2002).
65. Pasca MR, Guglierame P, Arcesi F, Bellinzoni M, De Rossi E, Riccardi G. Rv2686c-Rv2687c-Rv2688c, an ABC fluoroquinolone efflux pump in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 48(8), 3175-3178 (2004).
66. Danilchanka O, Mailaender C, Niederweis M. Identification of a novel multidrug efflux pump of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 52(7), 2503-2511 (2008).
67. Balganesh M, Kuruppath S, Marcel N, Sharma S, Nair A, Sharma U. Rv1218c, an ABC transporter of Mycobacterium tuberculosis with implications in drug discovery. Antimicrob. Agents Chemother. 54(12), 5167-5172 (2010).
68. Viveiros M, Jesus A, Brito M et al. Inducement and reversal of tetracycline resistance in Escherichia coli K-12 and expression of proton gradient-dependent multidrug efflux pump genes. Antimicrob. Agents Chemother. 49(8), 3578-3582 (2005).
69. Viveiros M, Dupont M, Rodrigues L et al. Antibiotic stress, genetic response and altered permeability of E. coli. PLoS ONE 2(4), e365 (2007).
70. Couto I, Costa SS, Viveiros M, Martins M, Amaral L. Efflux-mediated response of Staphylococcus aureus exposed to ethidium bromide. J. Antimicrob. Chemother. 62(3), 504-513 (2008).
71. Amaral L, Viveiros M, Kristiansen JE."Non-antibiotics": alternative therapy for the management of MDRTB and MRSA in economically disadvantaged countries. Curr. Drug Targets 7(7), 887-891 (2006).
72. Martins M, Dastidar SG, Fanning S et al. Potential role of non-antibiotics (helper compounds) in the treatment of multidrugresistant Gram-negative infections: mechanisms for their direct and indirect activities. Int. J. Antimicrob. Agents 31(3), 198-208 (2008).
73. Lomovskaya O, Bostian KA. Practical applications and feasibility of efflux pump inhibitors in the clinic Y a vision for applied use. Biochem. Pharmacol. 71(7), 910-918 (2006).
74. Pagès JM, Amaral L. Mechanisms of drug efflux and strategies to combat them: challenging the efflux pump of Gram-negative bacteria. Biochim. Biophys. Acta 1794(5), 826-833 (2009).
75. Marquez B. Bacterial efflux systems and efflux pumps inhibitors. Biochimie 87(12), 1137-1147 (2005).
76. Tegos GP, Haynes M, Strouse JJ et al. Microbial efflux pump inhibition: tactics and strategies. Curr. Pharm. Des. 17(13), 1291-1302 (2011).
77. Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria: an update. Drugs 69(12), 1555-1623 (2009).
78. Pagès JM, Amaral L, Fanning S. An original deal for new molecule: reversal of efflux pump activity, a rational strategy to combat gram-negative resistant bacteria. Curr. Med. Chem. 18(19), 2969-2980 (2011).
79. Kauffman GB. The discovery of iproniazid and its role in antidepressant therapy. J. Chem. Educ. 56, 35-36 (1979).
80. Cheifetz I, Paulin C, Tuatay H, Rubin EH. Iproniazid in pulmonary tuberculosis. Dis. Chest 25(4), 390-396 (1954).
81. Zeller EA. A new approach to the analysis of the interaction between monoamine oxidase and its substrates and inhibitors. Ann. N. Y. Acad. Sci. 107, 811-821 (1963).
82. Rollas S, Küçükgüzel SG. Biological activities of hydrazone derivatives. Molecules 12(8), 1910-1939 (2007).
83. Waxman S. In: From Neuroscience to Neurology: Neuroscience, Molecular Medicine, and the Therapeutic Transformation of Neurology. Elsevier Academic Press, VT, USA (2005).
84. Pocilowski O. Calcium channel antagonists in mood disorder. In: Antidepressants: New Pharmacological Strategies. Skolnick P. Humana Press Inc, NJ, USA, 81-102 (1997).
85. Yousef WM, Omar AH, Morsy MD, El-Wahed MMA, Ghanayem NM. The mechanism of action of calcium channel blockers in the treatment of diabetic nephropathy. Int. J. Diabetes Metabol. 13, 76-82 (2005).
86. Gangola P, Rosen BP. Maintenance of intracellular calcium in Escherichia coli. J. Biol. Chem. 262(26), 12570-12574 (1987).
87. McTavish D, Sorkin EM. Verapamil. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs 38(1), 19-76 (1989).
88. Andersen CL, Holland IB, Jacq A. Verapamil, a Ca2+ channel inhibitor acts as a local anesthetic and induces the sigma E dependent extra-cytoplasmic stress response in E. coli. Biochim. Biophys. Acta 1758(10), 1587-1595 (2006).
89. Endicott JA, Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu. Rev. Biochem. 58, 137-171 (1989).
90. 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. 61(5), 1076-1082 (2008).
91. Rodrigues L, Sampaio D, Couto I et al. The role of efflux pumps in macrolide resistance in Mycobacterium avium complex. Int. J. Antimicrob. Agents 34(6), 529-533 (2009).
92. Rodrigues LP, Iglesias D, Nicola FC et al. Transplantation of mononuclear cells from human umbilical cord blood promotes functional recovery after traumatic spinal cord injury in Wistar rats. Braz. J. Med. Biol. Res. 45(1), 49-57 (2012).
93. López-Muñoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G. History of the discovery and clinical introduction of chlorpromazine. Ann. Clin. Psychiatry 17(3), 113-135 (2005).
94. Amaral L, Kristiansen JE, Abebe LS, Millett W. 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. 38(6), 1049-1053 (1996).
95. Ordway O, Viveiros M, Leandro C, et al. Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 47(3), 917-922 (2003).
96. Martins M, Schelz Z, Martins A et al. In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis. Int. J. Antimicrob. Agents 29(3), 338-340 (2007).
97. Feinberg AP, Snyder SH. Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine. Proc. Nat. Acad. Sci. USA 72(5), 1899-1903 (1975).
98. Wetzel H, Gründer G, Hillert A et al. Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology Y a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist. The Amisulpride Study Group. Psychopharmacology (Berl.) 137(3), 223-232 (1998).
99. Kristiansen JE, Vergmann B. The antibacterial effect of selected phenothiazines and thioxanthenes on slow-growing mycobacteria. Acta Pathol. Microbiol. Immunol. Scand. B. 94(6), 393-398 (1986).
100. Beresford R, Ward A. Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis. Drugs 33(1), 31-49 (1987).
101. Dubinsky B, McGuire JL, Niemegeers CJ, Janssen PA, Weintraub HS, McKenzie BE. Bromperidol, a new butyrophenone neuroleptic: a review. Psychopharmacology (Berl.) 78(1), 1-7 (1982).
102. Ramón-García S, Ng C, Anderson H et al. Synergistic drug combinations for tuberculosis therapy identified by a novel high throughput screen. Antimicrob. Agents Chemother. 55(8), 3861-3869 (2011).
103. Deidda D, Lampis G, Fioravanti R et al. Bactericidal activities of the pyrrole derivative BM212 against multidrugresistant and intramacrophagic Mycobacterium tuberculosis strains. Antimicrob. Agents Chemother. 42(11), 3035-3037 (1998).
104. La Rosa V, Poce G, Canseco JO et al. MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob. Agents Chemother. 56(1), 324-331 (2012).
105. Lemieux G, Davignon A, Genest J. Depressive states during Rauwolfia therapy for arterial hypertension; a report of 30 cases. Can. Med. Assoc. J. 74(7), 522-526 (1956).
106. Balzer H, Makinose M, Fiehn W, Hasselbach W. The binding of the calcium transport inhibitors reserpine, chlorpromazine and prenylamine to the lipids of the membranes of the sarcoplasmic reticulum. Naunyn. Schmiedebergs. Arch. Exp. Pathol. Pharmakol. 260(5), 456-473 (1968).
107. Satoh T, Moriyama T, Kuriki H, Karaki H. Calcium channel blocker-like action of reserpine in smooth muscle. Jpn J. Pharmacol. 60(3), 291-293 (1992).
108. Zhang Y, Scorpio A, Nikaido H, Sun Z. Role of acid pH and deficient efflux of pyrazinoic acid in unique susceptibility of Mycobacterium tuberculosis to pyrazinamide. J. Bacteriol. 181(7), 2044-2049 (1999).
109. Begum S, Naqvi SQ, Ahmed A, Tauseef S, Siddiqui BS. Antimycobacterial and antioxidant activities of reserpine and its derivatives. Nat. Prod. Res. doi:10.1080/147 86419.2011.625502 (2012)(Epub ahead of print).
110. Grossman E, Messerli FH, Goldbourt U. Carcinogenicity of antihypertensive therapy. Curr. Hypertens. Rep. 4(3), 195-201 (2002).
111. Roullet JB, Luft UC, Xue H et al. Farnesol inhibits L-type Ca2+ channels in vascular smooth muscle cells. J. Biol. Chem. 272(51), 32240-32246 (1997).
112. Jin J, Zhang JY, Guo N et al. Farnesol, a potential efflux pump inhibitor in Mycobacterium smegmatis. Molecules 15(11), 7750-7762 (2010).
113. Koo H, Hayacibara MF, Schobel BD et al. Inhibition of Streptococcus mutans biofilm accumulation and polysaccharide production by apigenin and tt-farnesol. J. Antimicrob. Chemother. 52(5), 782-789 (2003).
114. Zhou FC, Tao-Cheng JH, Segu L, Patel T, Wang Y. Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence. Brain Res. 805(1-2), 241-254 (1998).
115. Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. Int. J. Antimicrob. Agents 14(3), 177-180 (2000).
116. Bohnert JA, Szymaniak-Vits M, Schuster S, Kern WV. Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli. J. Antimicrob. Chemother. 66(9), 2057-2060 (2011).
117. 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. 59(6), 1237-1246 (2007).
118. Martins M, Viveiros M, Couto I, Amaral L. Targeting human macrophages for enhanced killing of intracellular XDR-TB and MDR-TB. Int. J. Tuberc. Lung Dis. 13(5), 569-573 (2009).
119. Reeves EP, Lu H, Jacobs HL et al. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416(6878), 291-297 (2002).
120. Ahluwalia J, Tinker A, Clapp LH et al. The large-conductance Ca2+-activated K+channel is essential for innate immunity. Nature 427(6977), 853-858 (2004).
121. Amaral L, Viveiros M. Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections. Int. J. Antimicrob. Agents 39(5), 376-380 (2012).
122. Rodrigues L, Aínsa JA, Amaral L, Viveiros M. Inhibition of drug efflux in mycobacteria with phenothiazines and other putative efflux inhibitors. Recent Pat. Antiinfect. Drug Discov. 6(2), 118-127 (2011).
123. García JJ, Tuena de Gómez-Puyou M, Gómez-Puyou A. Inhibition by trifluoperazine of ATP synthesis and hydrolysis by particulate and soluble mitochondrial F1: competition with H2PO4-. J. Bioenerg. Biomembr. 27(1), 127-136 (1995).
124. Martins A, Machado L, Costa S et al. Role of calcium in the efflux system of Escherichia coli. Int. J. Antimicrob. Agents 37(5), 410-414 (2011).
125. Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D. Thioridazine cures extensively drugresistant tuberculosis (XDR-TB) and the need for global trials is now! Int. J. Antimicrob. Agents 35(6), 524-526 (2010).
126. Abbate E, Vescovo M, Natiello M et al. Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J. Antimicrob. Chemother. 67(2), 473-477 (2012).
127. Bhatt K, Banerjee SK, Chakraborti PK. Evidence that phosphate specific transporter is amplified in a fluoroquinolone resistant Mycobacterium smegmatis. Eur. J. Biochem. 267(13), 4028-4032 (2000).
128. Louw GE, Warren RM, Gey van Pittius NC et al. Rifampicin reduces susceptibility to ofloxacin in rifampicin-resistant Mycobacterium tuberculosis through efflux. Am. J. Respir. Crit. Care Med. 184(2), 269-276 (2011).