Review Article | Published:

Advances in the development of new tuberculosis drugs and treatment regimens

Nature Reviews Drug Discovery volume 12, pages 388404 (2013) | Download Citation


Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause considerable morbidity and mortality worldwide. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging. Such regimens are likely to utilize both repurposed drugs and new chemical entities, and several of these regimens are now progressing through clinical trials. This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

Key points

  • Despite the introduction 40 years ago of the inexpensive and effective four-drug (isoniazid, rifampicin, pyrazinamide and ethambutol) treatment regimen, tuberculosis (TB) continues to cause significant morbidity and mortality worldwide.

  • After five decades of near inactivity in TB drug development, the past 5 years has seen the development of a promising TB drug pipeline. For the first time since the 1960s, new and novel drugs and regimens for all forms of TB are emerging.

  • Several new TB drug candidates are in Phase II and Phase III clinical trials in addition to high activity in the hit-to-lead and lead optimization stages.

  • New TB drug development has led to the submission of two new TB drugs for regulatory approval: delamanid (also known as OPC67683) and bedaquiline (also known as TMC207 or R207910).

  • The US Food and Drug Administration recently approved bedaquiline as part of a combination therapy in the treatment of adults with multidrug-resistant TB.

  • New TB treatment regimens aimed at reducing the duration of chemotherapy or for use against drug-resistant TB using new chemical entities are now progressing through clinical trials.

  • Many of the candidates in clinical trials are drugs that were developed to treat other infectious diseases and have since been repurposed for TB (for example, fluoroquinolones, rifamycins, oxazolidinones and clofazimine).

  • Several newer approaches are currently being pursued with the aim of reducing the time required for evaluating new TB drugs through the various phases of clinical trials. These include the use of 14-day early bactericidal activity (EBA) studies to rapidly determine bactericidal activity, the use of innovative trial designs that include multi-arm, multi-stage determinations of efficacy of new drug combinations, and the exploration and qualification of new surrogate markers of treatment effect.

  • To facilitate this more rapid evaluation of new TB drugs, current clinical trials are initially testing new combinations of TB drugs in patients with drug-susceptible pulmonary TB.

  • This article covers current concepts and recent advances in TB drug discovery and development, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    , , & Tuberculosis. N. Engl. J. Med. 368, 745–755 (2013). An important update of current concepts on the clinical, epidemiological and management aspects of tuberculosis.

  2. 2.

    in Tuberculosis: A Comprehensive Clinical Reference (eds Schaaf, S. & Zumla, A. I.) 44–59 (Saunders, 2009).

  3. 3.

    , , , & Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA 282, 677–686 (1999).

  4. 4.

    et al. Old ideas to innovate TB control: preventive treatment to achieve elimination. Eur. Respir. J. 8 Feb 2013 (10.1183/09031936.00205512).

  5. 5.

    et al. Scaling up interventions to achieve global tuberculosis control: progress and new developments. Lancet 379, 1902–1913 (2012).

  6. 6.

    World Health Organization. Global Tuberculosis Report 2012 (WHO, 2012).

  7. 7.

    European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis Surveillance and Monitoring in Europe (European Centre for Disease Prevention and Control, 2012).

  8. 8.

    , & Modelling tuberculosis trends in the USA. Epidemiol. Infect. 140, 1862–1872 (2012).

  9. 9.

    Infectious disease. Approval of novel TB drug celebrated — with restraint. Science 339, 130 (2013).

  10. 10.

    World Health Organization. Treatment of Tuberculosis Guidelines 4th edn (WHO, 2010).

  11. 11.

    Tuberculosis Coalition for Technical Assistance. International Standards for Tuberculosis Care (ISTC) 2nd edn (Tuberculosis Coalition for Technical Assistance, 2009)

  12. 12.

    et al. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am. J. Respir. Crit. Care Med. 180, 558–563 (2009).

  13. 13.

    et al. Efficacy and safety of a 4-drug fixed-dose combination regimen compared with separate drugs for treatment of pulmonary tuberculosis: the study C randomized controlled trial. JAMA 305, 1415–1423 (2011).

  14. 14.

    et al. Old drugs, new purpose: retooling existing drugs for optimized treatment of resistant tuberculosis. Clin. Infect. Dis. 55, 572–581 (2012).

  15. 15.

    et al. WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur. Respir. J. 38, 516–528 (2011).

  16. 16.

    & Advances in tuberculosis diagnostics: the Xpert MTB/RIF assay and future prospects for a point-of-care test. Lancet Infect. Dis. 13, 349–361 (2013). A critical review of the Xpert MTB/RIF assay and the advantages and limitations of its utility in clinical practice.

  17. 17.

    et al. Rapid molecular TB diagnosis: evidence, policy-making and global implementation of Xpert®MTB/RIF. Eur. Respir. J. 22 Nov 2012 (10.1183/09031936.00157212).

  18. 18.

    et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet 368, 1575–1580 (2006).

  19. 19.

    et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet 375, 1798–1807 (2010).

  20. 20.

    , , , & Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clin. Infect. Dis. 51, 6–14 (2010).

  21. 21.

    et al. Drug resistance beyond XDR-TB: results from a large individual patient data meta-analysis. Eur. Respir. J. 11 Oct 2012 (10.1183/09031936.00136312).

  22. 22.

    , , & Totally drug-resistant tuberculosis in India. Clin. Infect. Dis. 54, 579–581 (2012).

  23. 23.

    World Health Organization. “Totally Drug-Resistant TB”: a WHO consultation on the diagnostic definition and treatment options. World Health Organization , (2012).

  24. 24.

    & New tuberculosis drugs on the horizon. Curr. Opin. Microbiol. 14, 570–576 (2011).

  25. 25.

    , , , & The challenge of new drug discovery for tuberculosis. Nature 469, 483–490 (2011).

  26. 26.

    Global-Alliance for TB Drug Development. Tuberculosis. Scientific blueprint for tuberculosis drug development. Tuberculosis (Edinb.) 81, (Suppl. 1), 1–52 (2001).

  27. 27.

    et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nature Rev. Microbiol. 7, 845–855 (2009).

  28. 28.

    , & Bactericidal and sterilizing activities of antituberculosis drugs during the first 14 days. Am. J. Respir. Crit. Care Med. 167, 1348–1354 (2003).

  29. 29.

    & The early bactericidal activity of anti-tuberculosis drugs: a literature review. Tuberculosis (Edinb.) 88, (Suppl. 1), 75–83 (2008).

  30. 30.

    et al. Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am. J. Respir. Crit. Care Med. 169, 421–426 (2004).

  31. 31.

    , , , & Global tuberculosis drug development pipeline: the need and the reality. Lancet 375, 2100–2109 (2010).

  32. 32.

    et al. Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med. 4, e344 (2007).

  33. 33.

    et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N. Engl. J. Med. 365, 2155–2166 (2011).

  34. 34.

    et al. Early bactericidal activity of high-dose rifampin in patients with pulmonary tuberculosis evidenced by positive sputum smears. Antimicrob. Agents Chemother. 51, 2994–2996 (2007).

  35. 35.

    et al. Why do we use 600 mg of rifampicin in tuberculosis treatment? Clin. Infect. Dis. 52, e194–e199 (2011).

  36. 36.

    et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223–227 (2005). A landmark paper describing the discovery and development of bedaquiline and the validation of a novel yet ubiquitous new drug target for TB.

  37. 37.

    et al. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J. Antimicrob. Chemother. 68, 284–293 (2013).

  38. 38.

    et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am. J. Respir. Crit. Care Med. 182, 684–692 (2010). An observational “Bangladesh” standardized regimen study, with a duration of 9–12 months, that included gatifloxacin, ethambutol, pyrazinamide and clofazimine throughout, supplemented by kanamycin, prothionamide and isoniazid. During an intensive phase of 4 months this regimen achieved <1% failure and 90% relapse-free cure.

  39. 39.

    et al. Inhaled microparticles containing clofazimine are efficacious in treatment of experimental tuberculosis in mice. Antimicrob. Agents Chemother. 57, 1050–1052 (2013).

  40. 40.

    et al. Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis. Antimicrob. Agents Chemother. 56, 5782–5789 (2012).

  41. 41.

    et al. Oxazolidinone, a new class of synthetic antituberculosis agent: in vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis. Diagn. Microbiol. Infect. Dis. 14, 465–471 (1991).

  42. 42.

    et al. Linezolid for the treatment of multidrug-resistant tuberculosis. J. Antimicrob. Chemother. 56, 180–185 (2005).

  43. 43.

    et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N. Engl. J. Med. 367, 1508–1518 (2012). A demonstration that linezolid, a drug with poor EBA, can improve the prognosis of patients with XDR-TB, thus providing hope that next-generation oxazolidinones may be even better.

  44. 44.

    et al. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur. Respir. J. 40, 1430–1442 (2012).

  45. 45.

    et al. Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis. Antimicrob. Agents Chemother. 55, 567–574 (2010).

  46. 46.

    et al. Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers. J. Infect. Dis. 202, 745–751 (2010).

  47. 47.

    et al. Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide. PLoS ONE 7, e30479 (2012).

  48. 48.

    et al. A 14-day multiple ascending dose study: AZD5847 is well tolerated at predicted exposure for treatment of tuberculosis (TB) (Abstract A1-1735). 51st Annual Interscience Conference on Antimicrobial Agents and Chemotherapy , (2011).

  49. 49.

    et al. Meropenem-clavulanate is effective against extensively drug-resistant Mycobacterium tuberculosis. Science 323, 1215–1218 (2009).

  50. 50.

    et al. Meropenem inhibits D,D-carboxypeptidase activity in Mycobacterium tuberculosis. Mol. Microbiol. 86, 367–381 (2012).

  51. 51.

    , , , & Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis. Pediatr. Infect. Dis. J. 30, 812–813 (2011).

  52. 52.

    et al. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur. Respir. J. 20 Sept 2012 (10.1183/09031936.00124312).

  53. 53.

    et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nature Chem. Biol. 3, 323–324 (2007).

  54. 54.

    et al. Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue. Antimicrob. Agents Chemother. 53, 1290–1292 (2009).

  55. 55.

    et al. Rates and mechanisms of resistance development in Mycobacterium tuberculosis to a novel diarylquinoline ATP synthase inhibitor. Antimicrob. Agents Chemother. 54, 1022–1028 (2009).

  56. 56.

    et al. Variations of subunit ε of the Mycobacterium tuberculosis F1F0 ATP synthase and a novel model for mechanism of action of the TB drug TMC207. Antimicrob. Agents Chemother. 57, 168–176 (2013).

  57. 57.

    et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J. Biol. Chem. 283, 25273–25280 (2008).

  58. 58.

    , , , & The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 105, 11945–11950 (2008).

  59. 59.

    et al. The diarylquinoline TMC207 for multidrug-resistant tuberculosis. N. Engl. J. Med. 360, 2397–2405 (2009). An important publication documenting the considerable impact of bedaquiline on the prognosis of patients with MDR-TB and the value of testing new drugs in MDR cohorts.

  60. 60.

    et al. A once-weekly R207910-containing regimen exceeds activity of the standard daily regimen in murine tuberculosis. Am. J. Respir. Crit. Care Med. 179, 75–79 (2009).

  61. 61.

    et al. Prevention of drug carryover effects in studies assessing antimycobacterial efficacy of TMC207. J. Clin. Microbiol. 46, 2212–2215 (2008).

  62. 62.

    et al. Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques. Proc. Natl Acad. Sci. USA 109, 14188–14193 (2012).

  63. 63.

    et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962–966 (2000).

  64. 64.

    et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 3, e466 (2006).

  65. 65.

    et al. Identification of a nitroimidazo-oxazine-specific protein involved in PA-824 resistance in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 103, 431–436 (2006).

  66. 66.

    et al. PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science 322, 1392–1395 (2008). An important publication documenting a novel M. tuberculosis killing mechanism mediated by PA-824 (and later by delaminid) that provides proof of concept for developing novel NO donor drugs for treating TB.

  67. 67.

    et al. Mycobacterium leprae is naturally resistant to PA-824. Antimicrob. Agents Chemother. 50, 3350–3354 (2006).

  68. 68.

    et al. A microbiological assessment of novel nitrofuranylamides as anti-tuberculosis agents. J. Antimicrob. Chemother. 62, 1037–1045 (2008).

  69. 69.

    , & The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun. Integr. Biol. 2, 215–218 (2009).

  70. 70.

    et al. Phase II dose-ranging trial of the early bactericidal activity of PA-824; Antimicrob. Agents Chemother. 56, 3027–3031 (2012).

  71. 71.

    et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 380, 986–993 (2012). A seminal study describing how the use of EBA with combination therapies has the potential to reduce the time needed for developing new multidrug regimens.

  72. 72.

    et al. Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients. Int. J. Tuberc. Lung Dis. 15, 949–954 (2011).

  73. 73.

    et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N. Engl. J. Med. 366, 2151–2160 (2012). An encouraging publication demonstrating that delamanid could enhance treatment options for patients with MDR-TB.

  74. 74.

    et al. Delamanid improves outcomes and reduces mortality for multidrug-resistant tuberculosis. Eur. Respir. J. 27 Sept 2012 (10.1183/09031936.00125812).

  75. 75.

    et al. Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J. Comb. Chem. 5, 172–187 (2003).

  76. 76.

    et al. SQ109 targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56, 1797–1809 (2012).

  77. 77.

    , , & In vitro interactions between new antitubercular drug candidates SQ109 and TMC207. Antimicrob. Agents Chemother. 54, 2840–2846 (2010).

  78. 78.

    et al. Inhibition of mycolic acid transport across the Mycobacterium tuberculosis plasma membrane. Nature Chem. Biol. 8, 334–341 (2012).

  79. 79.

    et al. MmpL3 is the cellular target of the antitubercular pyrrole derivative BM212. Antimicrob. Agents Chemother. 56, 324–331 (2012).

  80. 80.

    et al. Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. ACS Chem. Biol. 7, 1377–1384 (2012).

  81. 81.

    et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324, 801–804 (2009). A landmark paper presenting both a new chemical entity and a novel drug target for TB therapy.

  82. 82.

    et al. Clinical isolates of Mycobacterium tuberculosis in four European hospitals are uniformly susceptible to benzothiazinones. Antimicrob. Agents Chemother. 54, 1616–1618 (2010).

  83. 83.

    , & In vitro combination studies of benzothiazinone lead compound BTZ043 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56, 5790–5793 (2012).

  84. 84.

    et al. Structural basis for benzothiazinone-mediated killing of Mycobacterium tuberculosis. Sci. Transl. Med. 4, 150ra121 (2012).

  85. 85.

    et al. Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-β-d-ribose 2′-epimerase DprE1 of Mycobacterium tuberculosis. J. Am. Chem. Soc. 132, 13663–13665 (2010).

  86. 86.

    et al. Benzothiazinones are suicide inhibitors of mycobacterial decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase DprE1. J. Am. Chem. Soc. 134, 912–915 (2012).

  87. 87.

    et al. High content screening identifies decaprenyl-phosphoribose 2′ epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog. 5, e1000645 (2009).

  88. 88.

    et al. Leads for antitubercular compounds from kinase inhibitor library screens. Tuberculosis (Edinb.) 90, 354–360 (2010).

  89. 89.

    , & Timing of relapse in short-course chemotherapy trials for tuberculosis. Int. J. Tuberc. Lung Dis. 14, 241–242 (2010).

  90. 90.

    et al. A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lessons learnt from the gatifloxacin for TB (OFLOTUB) project. Trials 13, 61 (2012).

  91. 91.

    et al. Innovative trial designs are practical solutions for improving the treatment of tuberculosis. J. Infect. Dis. 205, (Suppl. 2), 250–257 (2012).

  92. 92.

    et al. Tuberculosis biomarkers discovery: developments, needs and challenges. Lancet Infect. Dis. 13, 362–372 (2013). An important review of the latest information on progress on TB biomarkers development.

  93. 93.

    et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect. Dis. 10, 387–394 (2010).

  94. 94.

    , , , & Immunological biomarkers of tuberculosis. Nature Rev. Immunol. 11, 343–354 (2011).

  95. 95.

    et al. Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances, and opportunities. J. Infect. Dis. 205 (Suppl. 2), 147–158 (2012).

  96. 96.

    et al. CDC/NIH Workshop. Tuberculosis biomarker and surrogate endpoint research roadmap. Am. J. Respir. Crit. Care Med. 184, 972–979 (2011).

  97. 97.

    et al. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk. Eur. Respir. J. 39, 1425–1431 (2012).

  98. 98.

    et al. Drug resistant tuberculosis: time for visionary political leadership. Lancet Infect. Dis. 24 Mar 2013 (10.1016/S1473-3099(13)70030-6).

  99. 99.

    , & Streptomycin, a substance exhibiting antibiotic activity against Gram-positive and Gram-negative bacteria. Proc. Soc. Exp. Biol. Med. 55, 66–69 (1944).

  100. 100.

    Pulmonary tuberculosis. N. Engl. J. Med. 235, 220–229 (1946).

  101. 101.

    Streptomycin in the treatment of pulmonary tuberculosis. A Medical Research Council investigation. BMJ 1, 382–386 (1949).

  102. 102.

    American Thoracic Society. Treatment of tuberculosis. Am. J. Respir. Crit. Care Med. 167, 603–662 (2003).

  103. 103.

    , , & Initiating antiretrovirals during tuberculosis treatment: a drug safety review. Expert Opin. Drug Saf. 10, 559–574 (2011).

  104. 104.

    et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N. Engl. J. Med. 365, 1482–1491 (2011).

  105. 105.

    et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N. Engl. J. Med. 365, 1471–1481 (2011).

  106. 106.

    & When to start ART in Africa — an urgent research priority. N. Engl. J. Med. 368, 886–889 (2013).

  107. 107.

    et al. Phosphodiesterase-4 inhibition alters gene expression and improves isoniazid-mediated clearance of Mycobacterium tuberculosis in rabbit lungs. PLoS Pathog. 7, e1002262 (2011).

  108. 108.

    et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148, 434–446 (2012).

  109. 109.

    , , , & Adjunctive TNF inhibition with standard treatment enhances bacterial clearance in a murine model of necrotic TB granulomas. PLoS ONE 7, e39680 (2012).

  110. 110.

    et al. Imatinib-sensitive tyrosine kinases regulate mycobacterial pathogenesis and represent therapeutic targets against tuberculosis. Cell Host Microbe 10, 475–485 (2012).

  111. 111.

    & Non-steroidal anti-inflammatory drugs for adjunctive tuberculosis treatment. J. Infect. Dis. 5 Apr 2013 (10.1093/infdis/jit153).

  112. 112.

    , & Enhanced killing of intracellular multidrug-resistant Mycobacterium tuberculosis by compounds that affect the activity of efflux pumps. J. Antimicrob. Chemother. 59, 1237–1246 (2007).

  113. 113.

    et al. Drug tolerance in replicating mycobacteria mediate macrophage-induced efflux mechanism. Cell 145, 39–53 (2011).

  114. 114.

    et al. Anthelmintic avermectins kill M. tuberculosis, including multidrug-resistant clinical strains. Antimicrob. Agents Chemother. 57, 1040–1046 (2013).

  115. 115.

    et al. Successful shortening of tuberculosis treatment using adjuvant host-directed therapy with FDA-approved phosphodiesterase inhibitors in the mouse model. PLoS ONE 7, e30749 (2012).

  116. 116.

    , , & Adjunct immunotherapies for tuberculosis. J. Infect. Dis. 205 (Suppl. 2), 325–334 (2012).

  117. 117.

    et al. Abelson tyrosine kinase controls phagosomal acidification required for killing of Mycobacterium tuberculosis in human macrophages. J. Immunol. 189, 4069–4078 (2012).

  118. 118.

    et al. Intracellular bacterial growth is controlled by a kinase network around PKB/AKT1. Nature. 450, 725–730 (2007).

  119. 119.

    & Tuberculosis — metabolism and respiration in the absence of growth. Nature Rev. Microbiol. 3, 70–80 (2005).

  120. 120.

    & in Bacterial Resistance to Antimicrobials 2nd Edn (eds Wax, R. G., Lewis, K., Salyers, A. A. & Taber, H.) 313–342 (CRC, 2008).

  121. 121.

    et al. Pyrazinamide inhibits trans-translation in Mycobacterium tuberculosis. Science 333, 1630–1632 (2011).

  122. 122.

    , , , & Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science 339, 88–91 (2013).

  123. 123.

    et al. gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis. J. Antimicrob. Chemother. 67, 1088–1093 (2012).

  124. 124.

    et al. Mutations in the rrs A1401G gene and phenotypic resistance to amikacin and capreomycin in Mycobacterium tuberculosis. Microb. Drug Resist. 18, 193–197 (2012).

  125. 125.

    et al. Structure–activity relationships among the kanamycin aminoglycosides: role of ring I hydroxyl and amino groups. Antimicrob. Agents Chemother. 56, 6104–6108 (2012).

  126. 126.

    Global Alliance for TB Drug Development. Cycloserine. Tuberculosis (Edinb.) 88, 100–101 (2008).

  127. 127.

    , , , & Structure of the Mycobacterium tuberculosis d-alanine:d-alanine ligase, a target of the antituberculosis drug d-cycloserine. Antimicrob. Agents Chemother. 55, 291–301 (2010).

  128. 128.

    et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 360, 528–534 (2002).

  129. 129.

    , et al. Higher-dose rifampin for the treatment of pulmonary tuberculosis: a systematic review. Int. J. Tuber. Lung Dis. 15, 305–316 (2011).

  130. 130.

    , et al. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proc. Natl Acad. Sci. USA 109, 11354–11359 (2012).

Download references


The work of S.T.C. is supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under the grant agreement number 260872. The work of A.Z. is supported by the Medical Research Council, UK, the European Union FP7, the European Developing Countries Clinical Trials Partnership, the National Institutes for Health Research (NIHR) University College London (UCL) Hospitals NHS Trust Biomedical Research Centre and the UBS Optimus Foundation, Switzerland. The work of P.N. is supported by the National Institutes of Health through National Institute of Allergy and Infectious Diseases funding (1R01AI104589), the Centers for Disease Control and Prevention TB Trials Consortium, and the Bill and Melinda Gates Foundation. Adam Zumla, UCL School of Pharmacy, UK, provided technical and administrative assistance.

Author information


  1. Center for Clinical Microbiology, Division of Infection and Immunity, University College London Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.

    • Alimuddin Zumla
  2. Division of Pulmonary and Critical Care, University of California, San Francisco at San Francisco General Hospital, 1001 Potrero Avenue, San Francisco, California 94110, USA.

    • Payam Nahid
  3. Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, SV-GHI-UPCOL, Station 19, CH-1015 Lausanne, Switzerland.

    • Stewart T. Cole


  1. Search for Alimuddin Zumla in:

  2. Search for Payam Nahid in:

  3. Search for Stewart T. Cole in:

Competing interests

Stewart T. Cole is named as the inventor on patents or patent applications related to the work in this article.

Corresponding author

Correspondence to Stewart T. Cole.


Multidrug-resistant TB

(MDR-TB). Tuberculosis (TB) caused by Mycobacterium tuberculosis bacilli that are resistant to at least isoniazid and rifampicin.

Extensively drug-resistant TB

(XDR-TB). Tuberculosis (TB) caused by Mycobacterium tuberculosis bacilli that are resistant to rifampicin, isoniazid, plus any fluoroquinolone and at least one of the three injectable second-line drugs: amikacin, kanamycin and capreomycin.

Directly observed therapy

(DOT). An approach to patient management that involves carers directly observing patients taking their tuberculosis drugs.

Drug-susceptible TB

Tuberculosis (TB) caused by Mycobacterium tuberculosis bacilli that is susceptible to first-line TB drugs.

Early bactericidal activity

(EBA). A commonly used assay in which the Mycobacterium tuberculosis bacilli load in sputum from the lungs of infected patients is periodically monitored for loss of viability, or culture conversion, using microbiological techniques. The duration of the assay has been extended from 7 days to 14 days since its conception.

Antiretroviral therapy

(ART). A combination of antiviral drugs used for treatment of diseases due to HIV.

Randomized, controlled clinical trial

The random allocation of patients to therapeutic regimens after enrolment. Assurances on strict adherence to interventions and minimizing losses from the trial population throughout treatment and follow-up are also key elements of randomized clinical trials.

Repurposed drugs

In this article, these are drugs that were developed to treat other diseases and have since been repurposed for treating tuberculosis.

Immune reconstitution inflammatory syndrome

Describes a collection of inflammatory disorders that are associated with the paradoxical worsening of pre-existing infectious conditions following the initiation of antiretroviral therapy in HIV-infected individuals.


A host or pathogen (for example, Mycobacterium tuberculosis) characteristic that is objectively measured and evaluated as an indicator of normal biological processes or pathogenic processes, or as an indicator of pharmacological responses to a therapeutic intervention.

Paucibacillary disease

Pulmonary tuberculosis with low Mycobacterium tuberculosis load in sputum.


Repositories that store biospecimens and data obtained from well-characterized patient cohorts who have had adequate follow-up for therapeutic failure and relapse. Biobanks will constitute a significant resource for the biomarker discovery field.

About this article

Publication history



Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing