Pyrazinamide (pyrazinamide) is a nicotinamide analog. As a unique treatment for tuberculosis, antimicrobial drugs have shortened the treatment time, improved the efficiency of treatment, and reduced the recurrence rate, which is different from other common anti-tuberculosis drugs by inhibiting multiple targets, such as energy production, reverse translation, and survival pantothenate/coenzyme A. Therefore, it is used as an irreplaceable part of the second-line treatment of multidrug-resistant tuberculosis. In recent years, a combination of multiple anti-tuberculosis drugs, such as pyrazinamide and rifampin, has been found to improve the radical cure rate of tuberculosis. This review discusses the recent developments in pyrazinamide.

Yunchang Yang, Fuyong Liu, Shiqi Li. Research progress of pyrazinamide in the treatment of drug-resistant tuberculosis. Academic Journal of Medicine & Health Sciences (2025), Vol. 6, Issue 2: 21-29. https://doi.org/10.25236/AJMHS.2025.060204.

[1] World Health Organization.Global tuberculosis report 2022[R/OL]. Geneva: World Health Organization, 2022. https://www.who.int/teams/global-tuberculosis-programme/TB-reports/global-tuberculosis-report-2022.

[2] Dalmer O, Walter E, Firma E. 1936. Merck in Darmstadt. Verfahren zur Herstellung von Abkömmlingen der Pyrazinmonocarbonsäure. Patentiert im Deutschen Reiche vom 8. Juli 1934 ab. Germany patent 632 257 Klasse 12 p Gruppe 6 M 127990 IV a/12 p.

[3] YEAGER RL, MUNROE WG, DESSAU FI. Pyrazinamide (aldinamide) in the treatment of pulmonary tuberculosis. Am Rev Tuberc. 1952 May;65(5):523-46. PMID: 14924175.

[4] MCCUNE RM Jr, TOMPSETT R. Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug-susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J Exp Med. 1956 Nov 1;104(5):737-62. doi: 10.1084/jem.104.5.737. PMID: 13367341; PMCID: PMC2136613.

[5] Guidelines for the Programmatic Management of Drug-Resistant Tuberculosis: 2011 Update. Geneva: World Health Organization; 2011. PMID: 23844450.

[6] Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, Mdluli KE, Nuermberger EL. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob Agents Chemother. 2011 Dec;55(12):5485-92. doi: 10.1128/AAC.05293-11. Epub 2011 Sep 19. PMID: 21930883; PMCID: PMC3232786.

[7] World Health Organization, Solans, Belén P., Béranger, Agathe, Radtke, Kendra, Mohamed, Ali. et al. (‎2022)‎. WHO operational handbook on tuberculosis: module 4: treatment: drug-susceptible tuberculosis treatment: web annex 1: clinical outcomes and pharmacokinetics of first-line drugs (‎rifampicin, isoniazid, ethambutol and pyrazinamide)‎ in children (‎< 18 years)‎ treated for drug-susceptible tuberculosis: systematic review and meta-analysis. World Health Organization. https://iris.who.int/handle/10665/354538.

[8] Zaw MT, Emran NA, Lin Z. Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. J Infect Public Health. 2018 Sep-Oct;11(5):605-610. doi: 10.1016/j.jiph.2018.04.005. Epub 2018 Apr 26. PMID: 29706316.

[9] Viader-Salvadó JM, Luna-Aguirre CM, Reyes-Ruiz JM, Valdez-Leal R, del Bosque-Moncayo Mde L, Tijerina-Menchaca R, Guerrero-Olazarán M. Frequency of mutations in rpoB and codons 315 and 463 of katG in rifampin- and/or isoniazid-resistant Mycobacterium tuberculosis isolates from northeast Mexico. Microb Drug Resist. 2003 Spring;9(1):33-8. doi: 10.1089/107662903764736328. PMID: 12705681.

[10] Prim RI, Schörner MA, Senna SG, Nogueira CL, Figueiredo AC, Oliveira JG, Rovaris DB, Bazzo ML. Molecular profiling of drug resistant isolates of Mycobacterium tuberculosis in the state of Santa Catarina, southern Brazil. Mem Inst Oswaldo Cruz. 2015 Aug;110(5):618-23. doi: 10.1590/0074-02760150100. Epub 2015 Jul 7. PMID: 26154743; PMCID: PMC4569824.

[11] JIA Ping-Ping,ZHANG Yi,PENG Shi-Ze,et al. Establishment of a mechanistic weight-exclusion system for rifampicin-based antituberculosis drugs[J]. Journal of Baotou Medical College,2012,28(2):1-4,9. DOI:10.3969/j.issn.1006-740X.2012.02.001.

[12] Vilchèze C, Jacobs WR Jr. Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis: Genes, Mutations, and Causalities. Microbiol Spectr. 2014 Aug;2(4):MGM2-0014-2013. doi: 10.1128/microbiolspec.MGM2-0014-2013. PMID: 26104204; PMCID: PMC6636829.

[13] GONG Lan,NIU Qun,WANG Nan,et al. Correlation of isoniazid resistance gene mutations in Mycobacterium tuberculosis with resistance to other antituberculosis drugs[J]. Journal of practical medicine,2023,39(11):1353-1358.DOI:10.3969/j.issn.1006-5725.2023.11.006.

[14] XUE Hu, QIN Chao, ZHANG Cailian. Progress of molecular mechanism of Mycobacterium tuberculosis resistance to isoniazid[J]. Jilin Medical Science,2014(14):3108-3110.

[15] Serio AW, Keepers T, Andrews L, Krause KM. Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation. EcoSal Plus. 2018 Nov;8(1). doi: 10.1128/ecosalplus.ESP-0002-2018. PMID: 30447062.

[16] PANG Maoyin,ZHANG Wenhong,CHEN Shu,et al. Correlation of Mycobacterium tuberculosis rpoB gene mutations with multidrug resistance and the degree of rifampicin resistance[J].Fudan Journal (Medical Edition),2004,31(3):228-230,238. DOI:10.3969/j.issn.1672-8467.2004.03.003.

[17] Agdamag DM, Kageyama S, Solante R, Espantaleon AS, Sangco JC, Suzuki Y. Characterization of clinical isolates of Mycobacterium tuberculosis resistant to drugs and detection of RpoB mutation in multidrug-resistant tuberculosis in the Philippines. Int J Tuberc Lung Dis. 2003 Nov;7(11):1104-8. PMID: 14598972.

[18] Jankute M, Cox JA, Harrison J, Besra GS. Assembly of the Mycobacterial Cell Wall. Annu Rev Microbiol. 2015;69:405-23. doi: 10.1146/annurev-micro-091014-104121. PMID: 26488279.

[19] Jankute M, Grover S, Rana AK, Besra GS. Arabinogalactan and lipoarabinomannan biosynthesis: structure, biogenesis and their potential as drug targets. Future Microbiol. 2012 Jan;7(1):129-47. doi: 10.2217/fmb.11.123. PMID: 22191451.

[20] Srivastava S, Ayyagari A, Dhole TN, Nyati KK, Dwivedi SK. emb nucleotide polymorphisms and the role of embB306 mutations in Mycobacterium tuberculosis resistance to ethambutol. Int J Med Microbiol. 2009 Apr;299(4):269-80. doi: 10.1016/j.ijmm.2008.07.001. Epub 2008 Nov 17. PMID: 19010731.

[21] Antimycobacterial Susceptibility Testing Group. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment. Eur Respir J. 2022 Apr 14;59(4):2200166. doi: 10.1183/13993003.00166-2022. PMID: 35422426; PMCID: PMC9059840.

[22] Che Y, Bo D, Lin X, Chen T, He T, Lin Y. Phenotypic and molecular characterization of pyrazinamide resistance among multidrug-resistant Mycobacterium tuberculosis isolates in Ningbo, China. BMC Infect Dis. 2021 Jun 25;21(1):605. doi: 10.1186/s12879-021-06306-1. PMID: 34171989; PMCID: PMC8228925.

[23] Lopez JM, Zimic M, Vallejos K, Sevilla D, Quispe-Carbajal M, Roncal E, Rodríguez J, Rodríguez J, Antiparra R, Arteaga H, Gilman RH, Maruenda H, Sheen P. Quantitative H Nuclear Magnetic Resonance Assay for the Rapid Detection of Pyrazinamide Resistance in Mycobacterium tuberculosis from Sputum Samples. J Clin Microbiol. 2023 May 23;61(5):e0152222. doi: 10.1128/jcm.01522-22. Epub 2023 Apr 18. PMID: 37071032; PMCID: PMC10204627.1

[24] Sheen P, Requena D, Gushiken E, Gilman RH, Antiparra R, Lucero B, Lizárraga P, Cieza B, Roncal E, Grandjean L, Pain A, McNerney R, Clark TG, Moore D, Zimic M. A multiple genome analysis of Mycobacterium tuberculosis reveals specific novel genes and mutations associated with pyrazinamide resistance. BMC Genomics. 2017 Oct 11;18(1):769. doi: 10.1186/s12864-017-4146-z. PMID: 29020922; PMCID: PMC5637355.

[25] Gopal P, Sarathy JP, Yee M, Ragunathan P, Shin J, Bhushan S, Zhu J, Akopian T, Kandror O, Lim TK, Gengenbacher M, Lin Q, Rubin EJ, Grüber G, Dick T. Pyrazinamide triggers degradation of its target aspartate decarboxylase. Nat Commun. 2020 Apr 3;11(1):1661. doi: 10.1038/s41467-020-15516-1. PMID: 32245967; PMCID: PMC7125159.

[26] Liu J, Shi W, Zhang S, Hao X, Maslov DA, Shur KV, Bekker OB, Danilenko VN, Zhang Y. Mutations in Efflux Pump Rv1258c (Tap) Cause Resistance to Pyrazinamide, Isoniazid, and Streptomycin in M. tuberculosis. Front Microbiol. 2019 Feb 19;10:216. doi: 10.3389/fmicb.2019.00216. PMID: 30837962; PMCID: PMC6389670.

[27] Mitchison DA. The action of antituberculosis drugs in short-course chemotherapy. Tubercle. 1985 Sep;66(3):219-25. doi: 10.1016/0041-3879(85)90040-6. PMID: 3931319.

[28] McDERMOTT W, TOMPSETT R. Activation of pyrazinamide and nicotinamide in acidic environments in vitro. Am Rev Tuberc. 1954 Oct;70(4):748-54. doi: 10.1164/art.1954.70.4.748. PMID: 13197751.

[29] Foster JW, Moat AG. Nicotinamide adenine dinucleotide biosynthesis and pyridine nucleotide cycle metabolism in microbial systems. Microbiol Rev. 1980 Mar;44(1):83-105. doi: 10.1128/mr.44.1.83-105.1980. PMID: 6997723; PMCID: PMC373235.

[30] Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Tukvadze N, Little B, Bernheim A, Read TD, Guarner J, Derendorf H, Peloquin CA, Blumberg HM, Vashakidze S. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis. Antimicrob Agents Chemother. 2017 May 24;61(6):e00226-17. doi: 10.1128/AAC.00226-17. PMID: 28373198; PMCID: 

[31] Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a review. Int J Tuberc Lung Dis. 2003 Jan;7(1):6-21. PMID: 12701830.

[32] Chellappa K, McReynolds MR, Lu W, Zeng X, Makarov M, Hayat F, Mukherjee S, Bhat YR, Lingala SR, Shima RT, Descamps HC, Cox T, Ji L, Jankowski C, Chu Q, Davidson SM, Thaiss CA, Migaud ME, Rabinowitz JD, Baur JA. NAD precursors cycle between host tissues and the gut microbiome. Cell Metab. 2022 Dec 6;34(12):1947-1959.e5. doi: 10.1016/j.cmet.2022.11.004. PMID: 36476934; PMCID: PMC9825113.

[33] Wang T, Jiao WW, Shen AD. Progress on mechanism of ethambutol resistance in Mycobacterium Tuberculosis. Yi Chuan. 2016 Oct 20;38(10):910-917. doi: 10.16288/j.yczz.16-111. PMID: 27806932.

[34] CAMPAGNA M, CALIX A, HAUSER G. Observations on the combined use of pyrazinamide (Aldinamide) and isoniazid in the treatment of pulmonary tuberculosis; a clinical study. Am Rev Tuberc. 1954 Mar;69(3):334-50. doi: 10.1164/art.1954.69.3.334. PMID: 13138868.

[35] Controlled trial of 6- and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. Tubercle. 1975 Jun;56(2):81-96. doi: 10.1016/0041-3879(75)90020-3. PMID: 1103400.

[36] Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid plus pyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months. Am Rev Respir Dis. 1977 May;115(5):727-35. doi: 10.1164/arrd.1977.115.5.727. PMID: 857713.

[37] Nuermberger E, Rosenthal I, Tyagi S, Williams KN, Almeida D, Peloquin CA, Bishai WR, Grosset JH. Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother. 2006 Aug;50(8):2621-5. doi: 10.1128/AAC.00451-06. PMID: 16870750; PMCID: PMC1538692.

[38] Williams K, Minkowski A, Amoabeng O, Peloquin CA, Taylor D, Andries K, Wallis RS, Mdluli KE, Nuermberger EL. Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother. 2012 Jun;56(6):3114-20. doi: 10.1128/AAC.00384-12. Epub 2012 Apr 2. PMID: 22470112; PMCID: PMC3370712.

[39] Tasneen R, Li SY, Peloquin CA, Taylor D, Williams KN, Andries K, Mdluli KE, Nuermberger EL. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob Agents Chemother. 2011 Dec;55(12):5485-92. doi: 10.1128/AAC.05293-11. Epub 2011 Sep 19. PMID: 21930883; PMCID: PMC3232786.

[40] Zhang N, Savic RM, Boeree MJ, Peloquin CA, Weiner M, Heinrich N, Bliven-Sizemore E, Phillips PPJ, Hoelscher M, Whitworth W, Morlock G, Posey J, Stout JE, Mac Kenzie W, Aarnoutse R, Dooley KE; Tuberculosis Trials Consortium (TBTC) and Pan African Consortium for the Evaluation of Antituberculosis Antibiotics (PanACEA) Networks. Optimising pyrazinamide for the treatment of tuberculosis. Eur Respir J. 2021 Jul 20;58(1):2002013. doi: 10.1183/13993003.02013-2020. PMID: 33542052; PMCID: PMC8371453.

[41] Diacon AH, Pym A, Grobusch M, Patientia R, Rustomjee R, Page-Shipp L, Pistorius C, Krause R, Bogoshi M, Churchyard G, Venter A, Allen J, Palomino JC, De Marez T, van Heeswijk RP, Lounis N, Meyvisch P, Verbeeck J, Parys W, de Beule K, Andries K, Mc Neeley DF. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N Engl J Med. 2009 Jun 4;360(23):2397-405. doi: 10.1056/NEJMoa0808427. PMID: 19494215

[42] Ibrahim M, Andries K, Lounis N, Chauffour A, Truffot-Pernot C, Jarlier V, Veziris N. Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis. Antimicrob Agents Chemother. 2007 Mar;51(3):1011-5. doi: 10.1128/AAC.00898-06. Epub 2006 Dec 18. PMID: 17178794; PMCID: PMC1803154.

[43] Chang KC, Leung CC, Yew WW, Leung EC, Leung WM, Tam CM, Zhang Y. Pyrazinamide may improve fluoroquinolone-based treatment of multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2012 Nov;56(11):5465-75. doi: 10.1128/AAC.01300-12. Epub 2012 Aug 6. PMID: 22869570; PMCID: PMC3486566.Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcántara F, Sánchez E, Sarria M, Becerra M, Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Kim JY, Farmer P. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med. 2003 Jan 9;348(2):119-28. doi: 10.1056/NEJMoa022928. PMID: 12519922.

[44] Mitnick C, Bayona J, Palacios E, Shin S, Furin J, Alcántara F, Sánchez E, Sarria M, Becerra M, Fawzi MC, Kapiga S, Neuberg D, Maguire JH, Kim JY, Farmer P. Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med. 2003 Jan 9;348(2):119-28. doi: 10.1056/NEJMoa022928. PMID: 12519922.

[45] Sankhe K, Khan T, Bhavsar C, Momin M, Omri A. Selective drug deposition in lungs through pulmonary drug delivery system for effective management of drug-resistant TB. Expert Opin Drug Deliv. 2019 May;16(5):525-538. doi: 10.1080/17425247.2019.1609937. Epub 2019 May 6. PMID: 31007100.

[46] Desai SK, Mondal D, Bera S. Polyurethane-functionalized starch nanocrystals as anti-tuberculosis drug carrier. Sci Rep. 2021 Apr 15;11(1):8331. doi: 10.1038/s41598-021-86767-1. PMID: 33859215; PMCID: PMC8050055.

[47] Fan C, Eedara BB, Sinha S, Uddin MKM, Doyle C, Banu S, Das SC. Triple combination dry powder formulation of pretomanid, moxifloxacin, and pyrazinamide for treatment of multidrug-resistant tuberculosis. Int J Pharm. 2024 Apr 10;654:123984. doi: 10.1016/j.ijpharm.2024.123984. Epub 2024 Mar 9. PMID: 38461874.

[48] Laohapojanart N, Ratanajamit C, Kawkitinarong K, Srichana T. Efficacy and safety of combined isoniazid-rifampicin-pyrazinamide-levofloxacin dry powder inhaler in treatment of pulmonary tuberculosis: A randomized controlled trial. Pulm Pharmacol Ther. 2021 Oct;70:102056. doi: 10.1016/j.pupt.2021.102056. Epub 2021 Jul 15. PMID: 34273498.

[49] Eedara BB, Tucker IG, Das SC. Phospholipid-based pyrazinamide spray-dried inhalable powders for treating tuberculosis. Int J Pharm. 2016 Jun 15;506(1-2):174-83. doi: 10.1016/j.ijpharm.2016.04.038. Epub 2016 Apr 28. PMID: 27091294.

[50] Rohde KH, Sorci L. The Prospective Synergy of Antitubercular Drugs With NAD Biosynthesis Inhibitors. Front Microbiol. 2021 Jan 26;11:634640. doi: 10.3389/fmicb.2020.634640. PMID: 33584600; PMCID: PMC7873932.

[51] Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, Samoilova A, Skornykova S, Tudor E, Variava E, Yablonskiy P, Everitt D, Wills GH, Sun E, Olugbosi M, Egizi E, Li M, Holsta A, Timm J, Bateson A, Crook AM, Fabiane SM, Hunt R, McHugh TD, Tweed CD, Foraida S, Mendel CM, Spigelman M; ZeNix Trial Team. Bedaquiline-Pretomanid-Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med. 2022 Sep 1;387(9):810-823. doi: 10.1056/NEJMoa2119430. PMID: 36053506; PMCID: PMC9490302.

[52] Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M; PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. doi: 10.1016/S1473-3099(16)30274-2. Epub 2016 Oct 26. PMID: 28100438; PMCID: PMC5159618.

[53] Singhal A, Jie L, Kumar P, Hong GS, Leow MK, Paleja B, Tsenova L, Kurepina N, Chen J, Zolezzi F, Kreiswirth B, Poidinger M, Chee C, Kaplan G, Wang YT, De Libero G. Metformin as adjunct antituberculosis therapy. Sci Transl Med. 2014 Nov 19;6(263):263ra159. doi: 10.1126/scitranslmed.3009885. PMID: 25411472.

[54] Bitar I, Medvecky M, Amlerova J, Papagiannitsis CC, Hrabak J. Frequency of mutations associated with resistance to first- and second-line drugs in multidrug-resistant Mycobacterium tuberculosis isolates. J Glob Antimicrob Resist. 2020 Sep;22:275-282. doi: 10.1016/j.jgar.2020.03.013. Epub 2020 Apr 1. PMID: 32247078.

[55] Dudley MZ, Sheen P, Gilman RH, Ticona E, Friedland JS, Kirwan DE, Caviedes L, Rodriguez R, Cabrera LZ, Coronel J, Grandjean L, Moore DAJ, Evans CA, Huaroto L, Chávez-Pérez V, Zimic M. Detecting Mutations in the Mycobacterium tuberculosis Pyrazinamidase Gene pncA to Improve Infection Control and Decrease Drug Resistance Rates in Human Immunodeficiency Virus Coinfection. Am J Trop Med Hyg. 2016 Dec 7;95(6):1239-1246. doi: 10.4269/ajtmh.15-0711. Epub 2016 Oct 24. PMID: 27928075; PMCID: PMC5154434.

[56] Chang KC, Leung CC, Yew WW, Lau TY, Tam CM. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. Am J Respir Crit Care Med. 2008 Jun 15;177(12):1391-6. doi: 10.1164/rccm.200802-355OC. Epub 2008 Apr 3. PMID: 18388355.

[57] Singh A, Somvanshi P, Grover A. Pyrazinamide drug resistance in RpsA mutant (∆438A) of Mycobacterium tuberculosis: Dynamics of essential motions and free-energy landscape analysis. J Cell Biochem. 2019 May;120(5):7386-7402. doi: 10.1002/jcb.28013. Epub 2018 Nov 2. PMID: 30390330.

[58] Dai H, Sinclair DA, Ellis JL, Steegborn C. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol Ther. 2018 Aug;188:140-154. doi: 10.1016/j.pharmthera.2018.03.004. Epub 2018 Mar 22. PMID: 29577959; PMCID: PMC6342514.