New patentable use of an old neuroleptic compound thioridazine to combat tuberculosis: A gene regulation perspective

Recent Patents on Anti-Infective Drug Discovery

Volumn 6, Issue 2, 2011, Pages 128-138

  Dutta, Noton K ^a   Mazumdar, Kaushiki ^b   Dastidar, Sujata G ^b   Karakousis, Petros C ^a,c   Amaral, Leonard ^d  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b JADAVPUR UNIVERSITY   (India)

^c JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

^d INSTITUTO DE HIGIENE E MEDICINA TROPICAL   (Portugal)

Author keywords

Cell envelope stress; Drug targets; Gene essentiality; Mycobacterium tuberculosis; Respiratory chain components; Sigma factor B; Thioridazine

Indexed keywords

SIGMA FACTOR; THIORIDAZINE;

ANTIBACTERIAL ACTIVITY; ARTICLE; BACTERIAL CELL WALL; BACTERIAL GENOME; BACTERIAL SURVIVAL; DRUG TARGETING; GENE CONTROL; GENE EXPRESSION REGULATION; HUMAN; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; OPERON; PATENT; PRIORITY JOURNAL; PROTEIN EXPRESSION; RESPIRATORY CHAIN; TUBERCULOSIS;

ANIMALS; ANTITUBERCULAR AGENTS; DRUG DISCOVERY; DRUG RESISTANCE, MULTIPLE, BACTERIAL; DRUG THERAPY, COMBINATION; EXTENSIVELY DRUG-RESISTANT TUBERCULOSIS; GENE EXPRESSION REGULATION, BACTERIAL; HUMANS; MYCOBACTERIUM TUBERCULOSIS; PATENTS AS TOPIC; THIORIDAZINE; TREATMENT OUTCOME; TUBERCULOSIS, MULTIDRUG-RESISTANT;

EID: 79959961390     PISSN: 1574891X     EISSN: None     Source Type: Journal    
DOI: 10.2174/157489111796064597     Document Type: Article

References (98)

1. Raviglione MC. The new stop TB strategy and the global plan to stop TB, 2006-2015. Bull World Health organ 2007; 85: 327.
2. Pepper DJ, Marais S, Wilkinson RJ, Bhaijee F, Maartens G, McIlleron H, et al. Clinical deterioration during antituberculosis treatment in Africa: Incidence, causes and risk factors. BMC Infect Dis 2010; 30:10-83.
3. O'Donnell MR, Padayatchi N, Master I, Osburn G, Horsburgh CR. Improved early results for patients with extensively drug-resistant tuberculosis and HIV in South Africa. Int J Tuberc Lung Dis 2009; 13: 855-1.
4. Kliiman K, Altraja A. Predictors of poor treatment outcome in multi- and extensively drug-resistant pulmonary TB. Eur Respir J 2009; 33: 1085-94.
5. Andersen P, Doherty TM. The success and failure of BCG- implications for a novel tuberculosis vaccine. Nat Rev Mol Cell Biol 2005; 3: 656-2.
6. WHO. Global tuberculosis control - epidemiology, strategy, financing. Global tuberculosis control: A short update to the 2009 report. Geneva: World Health Organization, 2009.
7. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, et al. Treatment outcomes among patients with multidrugresistant tuberculosis: Systematic review and meta-analysis. Lancet Infect Dis 2009; 9: 153-1.
8. Ma Z, Lienhardt C, McIlleron H, Nunn AJ, Wang X. Global tuberculosis drug development pipeline: The need and the reality. Lancet 2010; 375: 2100-9.
9. [9] Ginsberg AM. Tuberculosis drug development: Progress, challenges, and the road ahead. Tuberculosis (Edinb) 2010; 90:162-7.
10. Amaral L, Martins A, Molnar J, Kristiansen JE, Martins M, Viveiros M, et al. Phenothiazines, bacterial efflux pumps and targeting the macrophage for enhanced killing of intracellular XDRTB. In vivo 2010; 24(4): 409-24.
11. Russell DG, Barry CE 3rd, Flynn JL. Tuberculosis: What we don't know can, and does, hurt us. Science 2010; 328(5980): 852-6.
12. Gogerty, J.H. Enhanced learning ability by use of Thioridazine. US3879552 (1973).
13. Joachim, R. Organic compounds. US4387086 (1983).
14. Hsu, T.A., Taipei, TW. Treatment of coronavirus infection. US7544712 (2009).
15. 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 1996; 38(6):1049-3.
16. Ordway D, Viveiros M, Leandro C, Bettencourt R, Almeida J, Martins M, et al. Clinical concentrations of thioridazine kill intracellular multidrug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother 2003; 47: 917-2.
17. Amaral L, Martins M, Viveiros M, Molnar J, Kristiansen JE. Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps. Current Drug Targets 2008; 9: 816-9.
18. 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: 1237-6.
19. Martins M, Viveiros M, Kristiansen JE, Molnar J, Amaral L. The curative activity of thioridazine on mice infected with Mycobacterium tuberculosis. In vivo 2007; 21: 771-5.
20. van Soolingen D, Hernandez-Pando R, Orozco H, Aguilar D, Magis-Escurra C, Amaral L, et al. The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis. PLoS ONE 2010; 5(9): e12640.
21. Vanriet, D.D., Lee, R.B., Coffin, W.A. MDR efflux pumps. WO0179257 (2001).
22. De Souza, N.J., Patel, M.V., Gupte, S.V., Upadhyay, D.J., Shukla, M.C., Chaturvedi, N.C., Bhawsar, S.B., Nair, S.C., Jafri M.A., Khorakiwala, H.F. Inhibitors of cellular efflux pumps of microbes. AU8009101 (2002) & US2002177559 (2002).
23. Amaral L, Boeree MJ, Gillespie SH, Udwadia ZF, van Soolingen D. Thioridazine cures extensively drug-resistant tuberculosis (XDR-TB) and the need for global trials is now! Int J Antimicrob Agents 2010; 35(6): 524-6.
24. Boshoff HI, Myers TG, Copp BR, McNeil MR, Wilson MA, Barry CE 3rd. The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism: novel insights into drug mechanisms of action. J Biol Chem 2004; 279: 40174-4.
25. Dutta NK, Mehra S and Kaushal D. Mycobacterium tuberculosis sigma factor network responds to cell-envelope damage by the promising anti-mycobacterial thioridazine. PLoS ONE 2010; 5 (4): e10069.
26. Amaral L, Molnar J. Therapy of XDR TB with thioridazine a drug beyond patent protection but eligible for patent as new use. Recent Pat Antiinfect Drug Discov 2010; 5: 109-4.
27. Vohra R, Gupta M, Chaturvedi R, Singh Y. Attack on the scourge of tuberculosis: Patented drug targets. Recent Pat Antiinfect Drug Discov 2006; 1(1): 95-106.
28. Amaral L, Kristiansen JE, Viveiros M, Atouguia J. 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 2001; 47(5): 505-1.
29. Sassetti CM, Boyd DH, Rubin EJ. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol 2003; 48:77-4.
30. Lamichhane G, Zignol M, Blades NJ, Geiman DE, Dougherty A, Grosset J, et al. A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: Application to Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2003; 100:7213-8.
31. Lamichhane G, Bishai WR. Defining the 'survivasome' of Mycobacterium tuberculosis. Nat Med 2007; 13(3): 280-2.
32. Sassetti CM, Rubin EJ. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci USA 2003; 100:12989-4.
33. Rengarajan J, Bloom BR, Rubin EJ. Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc Natl Acad Sci USA 2005; 102: 8327-2.
34. Lamichhane G, Tyagi S, Bishai WR. Designer arrays for defined mutant analysis to detect genes essential for survival of Mycobacterium tuberculosis in mouse lungs. Infect Immun 2003; 73: 2533.
35. Jain SK, Hernandez-Abanto SM, Cheng Q-J, Singh P, Ly LH, Klinkenberg LG, et al. Accelerated detection of Mycobacterium tuberculosis genes essential for bacterial survival in guinea pigs, compared with mice. J Infect Dis 2007; 195:1634-2.
36. Be NA, Lamichhane G, Grosset J, Tyagi S, Cheng QJ, Kim KS, et al. Murine model to study the invasion and survival of Mycobacterium tuberculosis in the central nervous system. J Infect Dis 2008; 198:1520-8.
37. Dutta NK, Mehra S, Didier PJ, Roy CJ, Doyle L, Alvrrez XH, et al. Genetic requirements for the survival of tubercle bacilli in primates. J Infect Dis 2010; 201 (11): 1743-2.
38. Kristiansen JE, Hendricks O, Delvin T, Butterworth TS, Aagaard L, Christensen JB, et al. Reversal of resistance in microorganisms by help of non-antibiotics. J Antimicrob Chemother 2007; 59: 1271-9.
39. Dutta NK, Annadurai S, Mazumdar K, Dastidar SG, Kristiansen J, Molnar J, et al. Potential management of resistant microbial infections with a novel non-antibiotic: The anti-inflammatory drug diclofenac sodium. Int J Antimicrob Agents 2007; 30: 242-9.
40. Martins M, Dastidar SG, Fanning S, Kristiansen JE, Molnár J, Pagès JM, et al. Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: Mechanisms for their direct and indirect activities. Int J Antimicrob Agents 2008; 31: 198-8.
41. Mazumdar K, Dastidar SG, Park JH, Dutta NK. The antiinflammatory non-antibiotic helper compound diclofenac: An antibacterial drug target. Eur J Clin Microbiol Infect Dis 2009; 28: 881-1.
42. Mazumdar K, Kumar AK, Dutta NK, Potential role of the cardiovascular non-antibiotic (helper compound) amlodipine in the treatment of microbial infections: Scope and hope for the future. Int J Antimicrob Agents 2010; 6: 295-2.
43. Amaral L, Lorian V. Effects of chlorpromazine on the cell envelope proteins of Escherichia coli. Antimicrob Agents Chemother 1991; 35:1923-4.
44. Viveiros M, Amaral L. Enhancement of antibiotic activity against poly-drug resistant Mycobacterium tuberculosis by phenothiazines. Int J Antimicrob Agents 2001; 17: 225- 8.
45. Dutta NK, Mazumdar K, Dastidar SG, Park JH. Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice. Int J Antimicrob Agents 2007; 30:336.
46. Dutta NK, Mazumdar K, DasGupta A, Dastidar SG. Activity of the phenothiazine methdilazine alone or in combination with isoniazid or streptomycin against Mycobacterium tuberculosis in mice. J Med Microbiol 2009; 58: 1667-8.
47. 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: 1237-6.
48. + efflux pumps of the bacterium and the killing macrophage. Anti- InfAgents Med Chem 2008; 7: 63-2.
49. Sacchettini JC, Rubin EJ, Freundlich JS. Drugs versus bugs: In pursuit of the persistent predator Mycobacterium tuberculosis. Nat Rev Microbiol 2008; 6: 41-52.
50. Thioridazine. Handbook of Anti-Tuberculosis Agents. Tubercul (Edinb) 2008; 88: 164-7.
51. Christensen, J.B., Hendricks, O., Kristiansen, J.E. Composition useful for the preparation of a medicament in the treatment of a patient with a microbial infection comprises an antimicrobial agent and Thioridazine derivatives. WO05046694 (2005) US20070287702 (2007).
52. Sohaskey CD. Nitrate enhances the survival of Mycobacterium tuberculosis during inhibition of respiration. J Bacteriol 2008; 190: 2981-6.
53. Xie Z, Siddiqi N, Rubin EJ. Differential antibiotic susceptibilities of starved Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 2005; 49: 4778-80.
54. Martins M, Schelz Z, Martins A, Molnar J, Hajo G, Riedl Z, et al. In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis. Int J Antimicrob Agents 2007; 29: 338.
55. Bate AB, Kalin JH, Fooksman EM, Amorose E L, Price CM, Williams HM, et al. Synthesis and antitubercular activity of quaternized promazine and promethazine derivatives. Bioorg Med Chem Lett 2007; 17: 1346-8.
56. Rao SP, Alonso S, Rand L, Dick T, Pethe K. The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc Natl Acad Sci USA 2008; 105(33): 11945-0.
57. Kim, L., Peichung, H. Drug discovery and increased potency of antiseptics and disinfectants based on high extracellular pH, the disablement of cellular efflux pumps, and the unexpected synergism there between. US2003118541 (2003).
58. Thanacoody RH, Daly AK, Reilly JG, Ferrier IN, Thomas SH. Factors affecting drug concentrations and QT interval during thioridazine therapy. Clin Pharmacol Ther 2007; 82(5): 555-5.
59. Perry PJ, Alexander B, Liskow B, Lindsay DeVane C. Psychotropic Drug Handbook. 8th Ed. Lippincott Williams & Wilkins: Baltimore, 2006.
60. Udwadia ZF, Pinto LM, Uplekar MW. Tuberculosis management by private practitioners in Mumbai, India: Has anything changed in two decades. PLoS ONE 2010;5(8):e12023.
61. Abbate E, Vescoso M, Natiello M, Cufre M, Garcia A, Ambroggi M, et al. Tuberculosis extensamente resistente (XDR-TB) en Argentina: Aspectos destacbles epidemiologicos, bacteriologicos, terapeuticos y evolutivos. Revista Argentina de Medicina Respiratoria 2007; 1:19-5.
62. Lonetto M, Gribskov M, Gross CA. The sigma 70 family: Sequence conservation and evolutionary relationships. J Bacteriol 1992; 174: 3843-9.
63. Missiakas D, Raina S. The extracytoplasmic function sigma factors: Role and regulation. Mol Microbiol 1998; 28: 1059-6.
64. Gomez JE, Chen JM, Bishai WR. Sigma factors of Mycobacterium tuberculosis. Tuber Lung Dis 1997; 78: 175-3.
65. Kaushal D, Schroeder BG, Tyagi S, Yoshimatsu T, Scott C, Ko C, et al. Reduced immunopathology and mortality despite tissue persistence in a Mycobacterium tuberculosis mutant lacking alternative sigma factor, SigH. Proc Natl Acad Sci USA 2002; 99: 8330-5.
66. Manganelli R, Voskuil MI, Schoolnik GK, Dubnau E, Gomez M, Smith I. Role of the extracytoplasmic-function sigma factor sigma (H) in Mycobacterium tuberculosis global gene expression. Mol Microbiol 2002; 45: 365-4.
67. Mehra S, Kaushal D. Functional genomics reveals extended roles of the Mycobacterium tuberculosis stress response factor SigH, in response to oxidative stress. J Bacteriol 2009; 191: 3965-80.
68. Ohno H, Zhu G, Mohan VP, Chu D, Kohno S, Jacobs WR, Jr., et al. The effects of reactive nitrogen intermediates on gene expression in Mycobacterium tuberculosis. Cell Microbiol 2003; 5: 637-8.
69. Graham JE, Clark-Curtiss JE. Identification of Mycobacterium tuberculosis RNAs synthesized in response to phagocytosis by human macrophages by selective capture of transcribed sequences (SCOTS). Proc Natl Acad Sci USA 1999; 96: 11554-9.
70. Jensen-Cain DM, Quinn FD. Differential expression of sigE by Mycobacterium tuberculosis during intracellular growth. Microb Pathog 2001; 30:271-8.
71. Manganelli R, Voskuil MI, Schoolnik GK, Smith I. The Mycobacterium tuberculosis ECF sigma factor sigmaE: Role in global gene expression and survival in macrophages. Mol Microbiol 2001; 41: 423-37.
72. Pang X, Vu P, Byrd TF, Ghanny S, Soteropoulos P, Mukamolova GV, et al. Evidence for complex interactions of stress-associated regulons in an mprAB deletion mutant of Mycobacterium tuberculosis. Microbiology 2007; 153: 1229-42.
73. Fontán PA, Voskuil MI, Gomez M, Tan D, Pardini M, Manganelli R, et al. The Mycobacterium tuberculosis sigma factor sigmaB is required for full response to cell envelope stress and hypoxia in vitro, but it is dispensable for in vivo growth. J Bacteriol 2009; 191: 5628-3.
74. Lee JH, Karakousis PC, Bishai WR. Roles of SigB and SigF in the Mycobacterium tuberculosis sigma factor network. J Bacteriol 2008; 190: 699-7.
75. Provvedi R, Boldrin F, Falciani F, Palu G, Manganelli R. Global transcriptional response to vancomycin in Mycobacterium tuberculosis. Microb 2009; 155:1093-2.
76. Dupre JM, Matyi SA, Singh AK, Song Y, Zaman S, Horan S, et al. The diclofenac stimulon of Staphylococcus aureus. Amer Soc Microbiol-109th Gen Meeting. Philadelphia, USA 2009.
77. Bonde M, Højland DH, Kolmos HK, Kallipolitis BH, Klitgaard JK. Thioridazine affects transcription of genes involved in cell wall biosynthesis in methicillin resistant Staphylococcus aureus. FEMS Microb Let 2011; doi: 10.1111/j.1574-6968.2011.02255.x
78. Fontán PA, Aris V, Alvarez ME, Ghanny S, Cheng J, Soteropoulos P, et al. Mycobacterium tuberculosis sigma factor E regulon modulates the host inflammatory response. J Infect Dis 2008; 198(6): 877-85.
79. Rodrigue S, Provvedi R, Jacques PE, Gaudreau L, Manganelli R. The sigma factors of Mycobacterium tuberculosis. FEMS Microbiol Rev 2006; 30(6): 926-41.
80. Kobayashi R, Suzuki T, Yoshida M. Escherichia coli phage-shock protein A (PspA) binds to membrane phospholipids and repairs proton leakage of the damaged membranes. Mol Microbiol 2007; 66: 100-9.
81. Darwin KH, Lin G, Chen Z, Li H, Nathan CF. Characterization of a Mycobacterium tuberculosis proteasomal ATPase homologue. Mol Microbiol 2005; 55: 561-1.
82. Weinstein EA, Yano T, Li LS, Avarbock D, Avarbock A, et al. Inhibitors of type II NADH: Menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci USA 2005; 102: 4548-3.
83. Yano T, Li LS, Weinstein E, The JS, Rubin H. Steady-state kinetics and inhibitory action of antitubercular phenothiazines on Mycobacterium tuberculosis type-II NADH menaquinone oxidoreductase (NDH-2). J Biol Chem 2006; 281: 11456-3.
84. Mehra S, Dutta NK, Mollenkopf HJ, Kaushal D. MT2816 encodes a key Mycobacterium tuberculosis stress response factor. J Infect Dis 2010; 202: 943-3.
85. Sherrid AM, Rustad TR, Cangelosi GA, Sherman DR. Characterization of a Clp protease gene regulator and the reaeration response in Mycobacterium tuberculosis. PLoS ONE 2010; 5(7): e11622.
86. Barik S, Sureka K, Mukherjee P, Basu J, Kundu M. RseA, the SigE specific anti-sigma factor of Mycobacterium tuberculosis, is inactivated by phosphorylation-dependent ClpC1P2 proteolysis. Mol. Microbiol 2010; 75: 592-6.
87. Waddell SJ, Stabler RA, Laing K, Kremer L, Reynolds RC, Besra GS. The use of microarray analysis to determine the gene expression profiles of Mycobacterium tuberculosis in response to anti-bacterial compounds. Tubercul (Edinb) 2004; 84: 263-74.
88. Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan J.A, Monahan IM., et al. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: Insights into the phagosomal environment. J Exp Med 2003; 198: 693-704.
89. Stewart GR, Wernisch L, Stabler R, Mangan JA, Hinds J, Laing KG, et al. Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Microbiology 2002; 148: 3129-8.
90. Viveiros M, Leandro C, Amaral L. Mycobacterial efflux pumps and chemotherapeutic implications. Int J Antimicrob Agents 2003; 22: 274-8.
91. De Rossi E, Ainsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: An unresolved question. FEMS Microbiol Rev 2006; 30: 36-52.
92. Doucet-Populaire F, Buriankova K, Weiser J, Pernodet JL. Natural and acquired macrolide resistance in mycobacteria. Curr Drug Targets Infect Disord 2002; 2: 355-70.
93. Gupta AK, Katoch VM, Chauhan DS, Sharma R, Singh M, Venkatesan K, et al. Microarray analysis of efflux pump genes in multidrug-resistant Mycobacterium tuberculosis during stress induced by common anti-tuberculous drugs. Microb Drug Resist 2010; 16: 21-8.
94. Viveiros M, Martins M, Couto I, Kristiansen JE, Molnar J, Amaral L. The in vitro activity of phenothiazines against Mycobacterium avium: Potential of thioridazine for therapy of the co-infected AIDS patient. In vivo 2005; 19: 733-6.
95. Rodrigues L, Wagner D, Viveiros M, Sampaio D, Couto I, Vavra M, et al. Thioridazine and chlorpromazine inhibition of ethidium bromide efflux in Mycobacterium avium and Mycobacterium smegmatis. J Antimicrob Chemother 2008; 61(5): 1076-2.
96. Walsh GP, Tan EV, Dela Cruz EC, Abalos RM, Villahermosa LG, Young LJ, et al. The Philippine Cynomolgus monkey (Macaca fasicularis) provides a new nonhuman primate model of tuberculosis that resembles human disease. Nat Med 1996; 2: 430- 6.
97. Capuano SV 3rd, Croix DA, Pawar S, Zinovik A, Myers A, Lin PL, et al. Experimental Mycobacterium tuberculosis infection of Cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect Immun 2003; 71 (10): 5831-44.
98. Lin PL, Pawar S, Myers A, Pegu A, Fuhrman C, Reinhart TA, et al. Early events in Mycobacterium tuberculosis infection in Cynomolgus macaques. Infect Immun 2006; 74: 3790-3.