Esmail, H., Macpherson, L., Coussens, A. K. & Houben, R. Mind the gap – managing tuberculosis across the disease spectrum. EBioMedicine 78, 103928 (2022).
Imperial, M. Z. et al. A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. Nat. Med. 24, 1708–1715 (2018).
World Health Organization. Target regimen profile for tuberculosis treatment. https://www.who.int/publications/i/item/9789240081512 (Geneva, 2023).
Aldridge, B. B. et al. The Tuberculosis Drug Accelerator at year 10: what have we learned? Nat. Med. https://doi.org/10.1038/s41591-021-01442-2 (2021).
Berger, C. A. et al. Variation in tuberculosis treatment outcomes and treatment supervision practices in Uganda. J. Clin. Tuberc. Other Mycobact. Dis. 21, 100184 (2020).
World Health Organization. Global Tuberculosis Report 2023. https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023 (Geneva, 2023).
Kendall, E. A., Shrestha, S. & Dowdy, D. W. The epidemiological importance of subclinical tuberculosis. A critical reappraisal. Am. J. Respir. Crit. Care Med. 203, 168–174 (2021).
Barry, C. E. 3rd et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat. Rev. Microbiol. 7, 845–855 (2009).
Drain, P. K. et al. Incipient and subclinical tuberculosis: a clinical review of early stages and progression of infection. Clin. Microbiol. Rev. https://doi.org/10.1128/CMR.00021-18 (2018).
Emery, J. C. et al. Self-clearance of Mycobacterium tuberculosis infection: implications for lifetime risk and population at-risk of tuberculosis disease. Proc. Biol. Sci. 288, 20201635 (2021).
Zaidi, S. M. A. et al. Beyond latent and active tuberculosis: a scoping review of conceptual frameworks. EClinicalMedicine 66, 102332 (2023).
Richards, A. S. et al. Quantifying progression and regression across the spectrum of pulmonary tuberculosis: a data synthesis study. Lancet Glob. Health 11, e684–e692 (2023).
Frascella, B. et al. Subclinical tuberculosis disease-a review and analysis of prevalence surveys to inform definitions, burden, associations, and screening methodology. Clin. Infect. Dis. 73, e830–e841 (2021).
Long, R. et al. The association between phylogenetic lineage and the subclinical phenotype of pulmonary tuberculosis: a retrospective 2-cohort study. J. Infect. 88, 123–131 (2024).
Reed, M. B. et al. A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response. Nature 431, 84–87 (2004).
Stanley, S. et al. Identification of bacterial determinants of tuberculosis infection and treatment outcomes: a phenogenomic analysis of clinical strains. Lancet Microbe https://doi.org/10.1016/S2666-5247(24)00022-3 (2024).
Gagneux, S. Host–pathogen coevolution in human tuberculosis. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 850–859 (2012).
Stucki, D. et al. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages. Nat. Genet. 48, 1535–1543 (2016).
Malherbe, S. T. et al. PET/CT guided tuberculosis treatment shortening: a randomized trial. Preprint at medRxiv https://doi.org/10.1101/2024.10.03.24314723 (2024).
Zhao, L., Gao, F., Zheng, C. & Sun, X. The impact of optimal glycemic control on tuberculosis treatment outcomes in patients with diabetes mellitus: systematic review and meta-analysis. JMIR Public Health Surveill. 10, e53948 (2024).
Seddon, J. A., Chiang, S. S., Esmail, H. & Coussens, A. K. The wonder years: what can primary school children teach us about immunity to Mycobacterium tuberculosis? Front. Immunol. 9, 2946 (2018).
World Health Organization. WHO consolidated guidelines on tuberculosis, module 4: treatment, drug-susceptible tuberculosis treatment. https://www.who.int/publications/i/item/9789240048126 (Geneva, 2022).
Jain, S. K. et al. Tuberculous meningitis: a roadmap for advancing basic and translational research. Nat. Immunol. 19, 521–525 (2018).
Wasserman, S. & Harrison, T. S. Tuberculous meningitis – new approaches needed. N. Engl. J. Med. 389, 1425–1426 (2023).
Wasserman, S. et al. Advancing the chemotherapy of tuberculous meningitis: a consensus view. Lancet Infect. Dis. https://doi.org/10.1016/S1473-3099(24)00512-7 (2024).
Chabala, C. et al. Clinical outcomes in children living with HIV treated for non-severe tuberculosis in the SHINE Trial. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciae193 (2024).
Morey, S. S. ATS adopts diagnostic standards for tuberculosis. Am. Fam. Physician 63, 979–980 (2001).
Coussens, A. K. et al. Classification of early tuberculosis states to guide research for improved care and prevention: an international Delphi consensus exercise. Lancet Respir. Med. 12, 484–498 (2024).
Sossen, B. et al. The natural history of untreated pulmonary tuberculosis in adults: a systematic review and meta-analysis. Lancet Respir. Med. 11, 367–379 (2023).
Lau, A. et al. The radiographic and mycobacteriologic correlates of subclinical pulmonary TB in canada: a retrospective cohort study. Chest 162, 309–320 (2022).
Esmail, H. et al. High resolution imaging and five-year tuberculosis contact outcomes. Preprint at medRxiv https://doi.org/10.1101/2023.07.03.23292111 (2023).
Nathavitharana, R. R., Garcia-Basteiro, A. L., Ruhwald, M., Cobelens, F. & Theron, G. Reimagining the status quo: how close are we to rapid sputum-free tuberculosis diagnostics for all? EBioMedicine 78, 103939 (2022).
Ryckman, T. S., Dowdy, D. W. & Kendall, E. A. Infectious and clinical tuberculosis trajectories: Bayesian modeling with case finding implications. Proc. Natl Acad. Sci. USA 119, e2211045119 (2022).
Patterson, B. et al. Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status. Proc. Natl Acad. Sci. USA 121, e2314813121 (2024).
Nahid, P. et al. Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: treatment of drug-susceptible tuberculosis. Clin. Infect. Dis. 63, 853–867 (2016).
Dorman, S. E. et al. Four-month rifapentine regimens with or without moxifloxacin for tuberculosis. N. Engl. J. Med. 384, 1705–1718 (2021).
Fox, W., Ellard, G. A. & Mitchison, D. A. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946–1986, with relevant subsequent publications. Int. J. Tuberc. Lung Dis. 3, 231–279 (1999).
Merle, C. S. et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. N. Engl. J. Med. 372, 1677 (2015).
Gillespie, S. H. et al. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N. Engl. J. Med. 371, 1577–1587 (2014).
Jindani, A. et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N. Engl. J. Med. 371, 1599–1608 (2014).
Gopalan, N. et al. Predictors of unfavorable responses to therapy in rifampicin-sensitive pulmonary tuberculosis using an integrated approach of radiological presentation and sputum mycobacterial burden. PLoS ONE 16, e0257647 (2021).
Romanowski, K. et al. Predicting tuberculosis relapse in patients treated with the standard 6-month regimen: an individual patient data meta-analysis. Thorax 74, 291–297 (2019).
Campbell, J. R. et al. Association of indicators of extensive disease and rifampin-resistant tuberculosis treatment outcomes: an individual participant data meta-analysis. Thorax 79, 169–178 (2024).
Chang, K. C., Leung, C. C., Yew, W. W., Ho, S. C. & Tam, C. M. A nested case-control study on treatment-related risk factors for early relapse of tuberculosis. Am. J. Respir. Crit. Care Med 170, 1124–1130 (2004).
Canetti, G. The Tubercle Bacillus (Springer, 1955).
Koch, R. Die aetiologie der tuberculose. Berliner Klinische Wochenschrift Vol. 19, No. 15, 221–230 (1882).
Loring, W. W., Melvin, I., Vandiviere, H. M. & Willis, H. S. The death and resurrection of the tubercle bacillus. Trans. Am. Clin. Climatol. Assoc. 67, 132–138 (1955).
Mishra, S. & Saito, K. Clinically encountered growth phenotypes of tuberculosis-causing bacilli and their in vitro study: a review. Front. Cell Infect. Microbiol. 12, 1029111 (2022).
Wells, G. et al. Micro-computed tomography analysis of the human tuberculous lung reveals remarkable heterogeneity in 3D granuloma morphology. Am. J. Respir. Crit. Care Med. 204, 583–595 (2021).
Chen, R. Y. et al. Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis. Lancet Microbe https://doi.org/10.1016/S2666-5247(21)00058-6 (2021).
Prosser, G. et al. The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition. Microbes Infect. 19, 177–192 (2017).
Conradie, F. et al. Treatment of highly drug-resistant pulmonary tuberculosis. N. Engl. J. Med. 382, 893–902 (2020).
Goig, G. A. et al. Transmission as a key driver of resistance to the new tuberculosis drugs. N. Engl. J. Med. 392, 97–99 (2025).
Shaw, E. S. et al. Bedaquiline: what might the future hold? Lancet Microbe https://doi.org/10.1016/S2666-5247(24)00149-6 (2024).
Nimmo, C. et al. Evolution of Mycobacterium tuberculosis drug resistance in the genomic era. Front. Cell Infect. Microbiol. 12, 954074 (2022).
Perumal, R. et al. Baseline and treatment-emergent bedaquiline resistance in drug-resistant tuberculosis: a systematic review and meta-analysis. Eur. Respir. J. https://doi.org/10.1183/13993003.00639-2023 (2023).
Zhao, B. et al. Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China. Ann. Clin. Microbiol. Antimicrob. 23, 40 (2024).
Miotto, P., Cirillo, D. M., Schon, T. & Koser, C. U. The exceptions that prove the rule—a historical view of bedaquiline susceptibility. Genome Med. 16, 39 (2024).
Rockwood, N., Abdullahi, L. H., Wilkinson, R. J. & Meintjes, G. Risk factors for acquired rifamycin and isoniazid resistance: a systematic review and meta-analysis. PLoS ONE 10, e0139017 (2015).
Barilar, I. et al. CRyPTIC Consortium. Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach. Nat. Commun. 15, 488 (2024).
Sarathy, J. P. et al. Extreme drug tolerance of Mycobacterium tuberculosis in caseum. Antimicrob. Agents Chemother. 62, e02266–e02317 (2018).
Waller, N. J. E., Cheung, C. Y., Cook, G. M. & McNeil, M. B. The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis. Nat. Commun. 14, 1517 (2023).
Roemhild, R., Bollenbach, T. & Andersson, D. I. The physiology and genetics of bacterial responses to antibiotic combinations. Nat. Rev. Microbiol. https://doi.org/10.1038/s41579-022-00700-5 (2022).
Sullivan, G. J., Delgado, N. N., Maharjan, R. & Cain, A. K. How antibiotics work together: molecular mechanisms behind combination therapy. Curr. Opin. Microbiol. 57, 31–40 (2020).
Wang, Z. et al. Mode-of-action profiling reveals glutamine synthetase as a collateral metabolic vulnerability of M. tuberculosis to bedaquiline. Proc. Natl Acad. Sci. USA 116, 19646–19651 (2019).
Poulton, N. C. et al. Beyond antibiotic resistance: the whiB7 transcription factor coordinates an adaptive response to alanine starvation in mycobacteria. Cell Chem. Biol. https://doi.org/10.1101/2023.06.02.543512 (2023).
Morris, R. P. et al. Ancestral antibiotic resistance in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 102, 12200–12205 (2005).
Schrader, S. M. et al. Multiform antimicrobial resistance from a metabolic mutation. Sci. Adv. 7, eabh2037 (2021).
Dheda, K. et al. Multidrug-resistant tuberculosis. Nat. Rev. Dis. Primers 10, 22 (2024).
Li, S. et al. CRISPRi chemical genetics and comparative genomics identify genes mediating drug potency in Mycobacterium tuberculosis. Nat. Microbiol. 7, 766–779 (2022).
Eckartt, K. A. et al. Compensatory evolution in NusG improves fitness of drug-resistant M. tuberculosis. Nature 628, 186–194 (2024).
Dooley, K. E., Hanna, D., Mave, V., Eisenach, K. & Savic, R. M. Advancing the development of new tuberculosis treatment regimens: the essential role of translational and clinical pharmacology and microbiology. PLoS Med. 16, e1002842 (2019).
Xie, Y. L. et al. Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.abd7618 (2021).
Lin, P. L. et al. Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat. Med. 20, 75–79 (2014).
Ernest, J. P. et al. Development of new tuberculosis drugs: translation to regimen composition for drug-sensitive and multidrug-resistant tuberculosis. Annu. Rev. Pharmacol. Toxicol. 61, 495–516 (2021).
Sarathy, J. P. et al. A novel tool to identify bactericidal compounds against vulnerable targets in drug-tolerant M. tuberculosis found in caseum. mBio 14, e0059823 (2023).
Lovewell, R. R., Sassetti, C. M. & VanderVen, B. C. Chewing the fat: lipid metabolism and homeostasis during M. tuberculosis infection. Curr. Opin. Microbiol. 29, 30–36 (2016).
Gold, B. & Nathan, C. Targeting phenotypically tolerant Mycobacterium tuberculosis. Microbiol Spectr. https://doi.org/10.1128/microbiolspec.TBTB2-0031-2016 (2017).
Lanni, F. et al. Adaptation to the intracellular environment of primary human macrophages influences drug susceptibility of Mycobacterium tuberculosis. Tuberculosis 139, 102318 (2023).
Liu, Y. et al. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J. Exp. Med. 213, 809–825 (2016).
Perumal Kannabiran, B. et al. Safety and efficacy of 25 mg/kg and 35 mg/kg vs 10 mg/kg rifampicin in pulmonary TB: a phase IIb randomized controlled trial. Open Forum Infect. Dis. 11, ofae034 (2024).
Onorato, L. et al. Standard versus high dose of rifampicin in the treatment of pulmonary tuberculosis: a systematic review and meta-analysis. Clin. Microbiol Infect. 27, 830–837 (2021).
Espinosa-Pereiro, J. et al. Safety of rifampicin at high dose for difficult-to-treat tuberculosis: protocol for RIAlta phase 2b/c trial. Pharmaceutics https://doi.org/10.3390/pharmaceutics15010009 (2022).
Diacon, A. H. 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).
Yun, H. Y. et al. Model-based efficacy and toxicity comparisons of moxifloxacin for multidrug-resistant tuberculosis. Open Forum Infect. Dis. 9, ofab660 (2022).
Kusmiati, T. et al. Moxifloxacin concentration correlate with QTc interval in rifampicin-resistant tuberculosis patients on shorter treatment regimens. J. Clin. Tuberc. Other Mycobact. Dis. 28, 100320 (2022).
Chang, A. et al. Circulating cell-free RNA in blood as a host response biomarker for the detection of tuberculosis. Nat. Commun. https://doi.org/10.1038/s41467-024-49245-6 (2023).
Zhang, F., Zhang, F., Dong, Y., Li, L. & Pang, Y. New insights into biomarkers for evaluating therapy efficacy in pulmonary tuberculosis: a narrative review. Infect. Dis. Ther. 12, 2665–2689 (2023).
Corrigan, D. T., Ishida, E., Chatterjee, D., Lowary, T. L. & Achkar, J. M. Monoclonal antibodies to lipoarabinomannan/arabinomannan – characteristics and implications for tuberculosis research and diagnostics. Trends Microbiol. 31, 22–35 (2023).
Gong, X., He, Y., Zhou, K., Hua, Y. & Li, Y. Efficacy of Xpert in tuberculosis diagnosis based on various specimens: a systematic review and meta-analysis. Front. Cell Infect. Microbiol. 13, 1149741 (2023).
Tabone, O. et al. Blood transcriptomics reveal the evolution and resolution of the immune response in tuberculosis. J. Exp. Med. https://doi.org/10.1084/jem.20210915 (2021).
Pierneef, L. et al. Host biomarker-based quantitative rapid tests for detection and treatment monitoring of tuberculosis and COVID-19. iScience 26, 105873 (2023).
Paton, N. I. et al. Treatment strategy for rifampin-susceptible tuberculosis. N. Engl. J. Med. 388, 873–887 (2023).
Hermans, S., Horsburgh, C. R. Jr. & Wood, R. A century of tuberculosis epidemiology in the northern and southern hemisphere: the differential impact of control interventions. PLoS ONE 10, e0135179 (2015).
Gillespie, S. H. et al. Developing biomarker assays to accelerate tuberculosis drug development: defining target product profiles. Lancet Microbe https://doi.org/10.1016/S2666-5247(24)00085-5 (2024).
Moyo, S. et al. Prevalence of bacteriologically confirmed pulmonary tuberculosis in South Africa, 2017-19: a multistage, cluster-based, cross-sectional survey. Lancet Infect. Dis. 22, 1172–1180 (2022).
Johnson, J. L. et al. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am. J. Respir. Crit. Care Med 180, 558–563 (2009).
A controlled trial of 3-month, 4-month, and 6-month regimens of chemotherapy for sputum-smear-negative pulmonary tuberculosis. Results at 5 years. Hong Kong Chest Service/Tuberculosis Research Centre, Madras/British Medical Research Council. Am. Rev. Respir. Dis. 139, 871–876 (1989).
Teo, S. K., Tan, K. K. & Khoo, T. K. Four-month chemotherapy in the treatment of smear-negative pulmonary tuberculosis: results at 30 to 60 months. Ann. Acad. Med. Singap. 31, 175–181 (2002).
James, L. P. et al. Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: a mathematical modeling analysis. PLoS Med. 21, e1004401 (2024).
Knight, G. M. et al. The impact and cost-effectiveness of a four-month regimen for first-line treatment of active tuberculosis in South Africa. PLoS ONE 10, e0145796 (2015).
Goh, J. J. N. et al. Prospectively predicting BPaMZ phase IIb/III trial outcomes using a translational mouse-to-human platform. Antimicrob. Agents Chemother. 68, e0061524 (2024).
Walter, N. D. et al. Mycobacterium tuberculosis precursor rRNA as a measure of treatment-shortening activity of drugs and regimens. Nat. Commun. 12, 2899 (2021).
Zainabadi, K. et al. Transcriptional biomarkers of differentially detectable mycobacterium tuberculosis in patient sputum. mBio 13, e0270122 (2022).
Zainabadi, K. et al. Characterization of differentially detectable mycobacterium tuberculosis in the sputum of subjects with drug-sensitive or drug-resistant tuberculosis before and after two months of therapy. Antimicrob. Agents Chemother. 65, e0060821 (2021).
Peters, J. S. et al. Differentially culturable tubercle bacteria as a measure of tuberculosis treatment response. Front. Cell Infect. Microbiol. 12, 1064148 (2022).
Fox, W. Whither short-course chemotherapy? Br. J. Dis. Chest 75, 331–357 (1981).
