Thioridazine: a potential adjuvant in pharmacotherapy of drug resistant tuberculosis Ki


  • Kiran K. Kishore Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
  • G. S. H. Ramakanth Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
  • N. Chandrasekhar Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
  • P. V. Kishan Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
  • Uday Kumar Chiranjeevi Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India
  • P. Usharani Department of Clinical Pharmacology & Therapeutics, Nizam’s Institute of Medical Sciences, Hyderabad, Telangana, India


Tuberculosis, Drug-resistant tuberculosis, Thioridazine


Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Despite advances in control strategies, inadequate treatment and failure to comply with drug regimens have resulted in TB to emerge as one of the most common and deadly infectious diseases worldwide. The emergence of drug-resistant TBhas evolved as a formidable obstacle for comprehensive TB control. Drug-resistant TB can be classified as multi-drug-resistant TB, extensively drug-resistant TB and totally drug resistant TB (TDR-TB). There is a paucity in the development of new drugs against drug-resistant mycobacteria. The focus has shifted to the exploration of anti-mycobacterial properties of drugs approved for other indications. Thioridazine, a drug approved for use in schizophrenia is one such potential agent, which has shown anti-mycobacterial activity. There is evidence of anti-mycobacterial action of Thioridazine in in-vitro and mouse models. There is a compelling need for new anti-mycobacterial drugs that are more effective and have less toxicity. Further clinical trials are advocated favoring the use of thioridazine as an adjuvant in the treatment of TB, especially TDR-TB.


World Health Organisation. Global Tuberculosis Report 2013. Available at: [Accessed on 2014 Aug 08].

Lawn SD, Zumla AI. Tuberculosis. Lancet. 2011;378:57-72.

Extensively drug-resistant tuberculosis (XDR-TB): Recommendations for prevention and control. Wkly Epidemiol Rec. 2006;81:430-2.

Centers for Disease Control and Prevention. Revised definition of extensively drug resistant tuberculosis. Morb Mortal Wkly Rep. 2006;55:1176.

Velayati AA, Masjedi MR, Farnia P, Tabarsi P, Ghanavi J, Ziazarifi AH, 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. 2009;136(2):420-5.

Migliori GB, De Iaco G, Besozzi G, Centis R, Cirillo DM. First tuberculosis cases in Italy resistant to all tested drugs. Euro Surveill. 2007;12(5):E070517.1.

Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis. 2012 15;54:579-81.

Almeida Da Silva PE, Palomino JC. Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs. J Antimicrob Chemother. 2011;66(7):1417-30.

Jarlier V, Nikaido H. Mycobacterial cell wall: structure and role in natural resistance to antibiotics. FEMS Microbiol Lett. 1994;123(1-2):11-8.

De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question. FEMS Microbiol Rev. 2006;30(1):36-52.

Pleasure H. Chlorpromazine (thorazine) for mental illness in the presence of pulmonary tuberculosis. Psychiatr Q. 1956;30(1):23-30.

Fisher RA, Teller E. Clinical experience with ataractic therapy in tuberculous psychiatric patients. Dis Chest. 1959;35(2):134-9.

Wainwright M, Amaral L, Kristiansen JE. The evolution of antimycobacterial agents from non-antibiotics. Open J Pharmacol. 2012; 2-1.

Miller R. Mechanisms of action of antipsychotic drugs. Curr Neuropharmacol. 2009;7:302-14.

Zhang Y, Heym B, Allen B, Young D, Cole S. The catalase peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis. Nature. 1992;358(6387):591 3.

Lee AS, Teo AS, Wong SY. Novel mutations in NDH in isoniazid-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2001;45(7):2157-9.

Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263(5144):227-30.

Slayden RA, Barry CE 3rd. The genetics and biochemistry of isoniazid resistance in Mycobacterium tuberculosis. Microbes Infect. 2000;2:659-69.

Sherman DR, Mdluli K, Hickey MJ, Arain TM, Morris SL, Barry CE 3rd, et al. Compensatory ahpC gene expression in isoniazid-resistant Mycobacterium tuberculosis. Science. 1996;272(5268):1641-3.

Zhang Y. The magic bullets and tuberculosis drug targets. Annu Rev Pharmacol Toxicol. 2005;45:529-64.

Ramaswamy S, Musser JM. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber Lung Dis. 1998;79(1):3 29.

Rattan A, Kalia A, Ahmad N. Multidrug-resistant Mycobacterium tuberculosis: molecular perspectives. Emerg Infect Dis. 1998;4:195-209.

Taniguchi H, Aramaki H, Nikaido Y, Mizuguchi Y, Nakamura M, Koga T, et al. Rifampicin resistance and mutation of the rpoB gene in Mycobacterium tuberculosis. FEMS Microbiol Lett. 1996;144:103-8.

Scorpio A, Zhang Y. Mutations in pncA, a gene encoding pyrazinamidase/nicotinamidase, cause resistance to the antituberculous drug pyrazinamide in tubercle bacillus. Nat Med. 1996;2(6):662-7.

Louw GE, Warren RM, Donald PR, Murray MB, Bosman M, Van Helden PD, et al. Frequency and implications of pyrazinamide resistance in managing previously treated tuberculosis patients. Int J Tuberc Lung Dis. 2006;10(7):802 7.

Gillespie SH. Evolution of drug resistance in Mycobacterium tuberculosis: clinical and molecular perspective. Antimicrob Agents Chemother. 2002;46(2):267-74.

Okamoto S, Tamaru A, Nakajima C, Nishimura K, Tanaka Y, Tokuyama S, et al. Loss of a conserved 7-methylguanosine modification in 16S rRNA confers low-level streptomycin resistance in bacteria. Mol Microbiol. 2007;63(4):1096-106.

Migliori GB, Besozzi G, Girardi E, Kliiman K, Lange C, Toungoussova OS, et al. Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J. 2007;30(4):623-6.

Telenti A, Philipp WJ, Sreevatsan S, Bernasconi C, Stockbauer KE, Wieles B, et al. The emb operon, a gene cluster of Mycobacterium tuberculosis involved in resistance to ethambutol. Nat Med. 1997;3(5):567-70.

Johnson R, Jordaan AM, Pretorius L, Engelke E, van der Spuy G, Kewley C, et al. Ethambutol resistance testing by mutation detection. Int J Tuberc Lung Dis. 2006;10(1):68 73.

Takiff HE, Salazar L, Guerrero C, Philipp W, Huang WM, Kreiswirth B, et al. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob Agents Chemother. 1994;38(4):773-80.

Ginsburg AS, Grosset JH, Bishai WR. Fluoroquinolones, tuberculosis, and resistance. Lancet Infect Dis. 2003;3(7):432-42.

Alangaden GJ, Kreiswirth BN, Aouad A, Khetarpal M, Igno FR, Moghazeh SL, et al. Mechanism of resistance to amikacin and kanamycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1998;42(5):1295-7.

Suzuki Y, Katsukawa C, Tamaru A, Abe C, Makino M, Mizuguchi Y, et al. Detection of kanamycin-resistant Mycobacterium tuberculosis by identifying mutations in the 16S rRNA gene. J Clin Microbiol. 1998;36(5):1220-5.

Krüüner A, Jureen P, Levina K, Ghebremichael S, Hoffner S. Discordant resistance to kanamycin and amikacin in drug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2003;47(9):2971-3.

Johansen SK, Maus CE, Plikaytis BB, Douthwaite S. Capreomycin binds across the ribosomal subunit interface using tlyA-encoded 2’-O-methylations in 16S and 23S rRNAs. Mol Cell. 2006;23(2):173-82.

Maus CE, Plikaytis BB, Shinnick TM. Mutation of tlyA confers capreomycin resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2005;49(2):571-7.

Baulard AR, Betts JC, Engohang-Ndong J, Quan S, McAdam RA, Brennan PJ, et al. Activation of the pro-drug ethionamide is regulated in mycobacteria. J Biol Chem 2000;275:28326-31.

Lee H, Cho SN, Bang HE, Lee JH, Bai GH, Kim SJ, et al. Exclusive mutations related to isoniazid and ethionamide resistance among Mycobacterium tuberculosis isolates from Korea. Int J Tuberc Lung Dis. 2000;4(5):441-7.

Morlock GP, Metchock B, Sikes D, Crawford JT, Cooksey RC. ethA, inhA, and katG loci of ethionamide-resistant clinical Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother. 2003;47:3799-805.

Rengarajan J, Sassetti CM, Naroditskaya V, Sloutsky A, Bloom BR, Rubin EJ. The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria. Mol Microbiol. 2004;53(1):275-82.

Amaral L, Fanning S, Pagès 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.

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. 2011;18:2969-80.

Amaral L. Totally drug resistant tuberculosis can be treated with thioridazine in combination with antibiotics to which the patient was initially resistant. Biochem Pharmacol. 2012;1:e102.

Weinstein EA, Yano T, Li LS, Avarbock D, Avarbock A, Helm D, et al. Inhibitors of type II NADH: menaquinone oxidoreductase represent a class of antitubercular drugs. Proc Natl Acad Sci U S A. 2005;102:4548-53.

Kaminska M. Role of chlorpromazine in the treatment of pulmonary tuberculosis in psychiatric patients. Folia Med Cracov. 1967;9(1):115-43.

Crowle AJ, Douvas GS, May MH. Chlorpromazine: a drug potentially useful for treating mycobacterial infections. Chemotherapy. 1992;38(6):410-9.

Molnár J, Béládi I, Földes I. Studies on antituberculotic action of some phenothiazine derivatives in vitro. Zentralbl Bakteriol Orig A,: 1977;239(4):521-6.

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):505-11.

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):1049-53.

Bettencourt MV, Bosne-David S, Amaral L. Comparative in vitro activity of phenothiazines against multidrug-resistant Mycobacterium tuberculosis. Int J Antimicrob Agents. 2000;16(1):69-71.

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.

Cardona PJ. Understanding Tuberculosis - New Approaches to Fighting Against Drug Resistance [internet]. London: Kolyva AS, Karakousis PC; 2012. Chapter 9, Old and new TB drugs. Available from: [Cited 2012 Feb 15].

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).

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.

Abbate E, Vescovo M, Natiello M, Cufré M, García A, Gonzalez Montaner P, et al. Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother. 2012;67(2):473-7.

Udwadia ZF, Sen T, Pinto LM. Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB. Recent Pat Antiinfect Drug Discov. 2011;6(2):88-91.

Boeree MJ. Global clinical trials for the treatment of TB with thioridazine. Recent Pat Antiinfect Drug Discov. 2011;6(2):99-103.




How to Cite

Kishore, K. K., Ramakanth, G. S. H., Chandrasekhar, N., Kishan, P. V., Chiranjeevi, U. K., & Usharani, P. (2017). Thioridazine: a potential adjuvant in pharmacotherapy of drug resistant tuberculosis Ki. International Journal of Basic & Clinical Pharmacology, 3(6), 928–932. Retrieved from



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