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Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease

Nature Reviews Drug Discovery (2024)Cite this article

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Abstract

Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public–private partnerships and sustained funding have delivered a much-improved understanding of mycobacterial disease biology and pharmacology and a healthy pipeline that can tolerate inevitable attrition. Preclinical and clinical development has evolved from decade-old concepts to adaptive designs that permit rapid evaluation of regimens that might greatly shorten treatment duration over the next decade. But the past 20 years also saw the rise of a fatal and difficult-to-cure lung disease caused by nontuberculous mycobacteria (NTM), for which the drug development pipeline is nearly empty. Here, we discuss the similarities and differences between TB and NTM lung diseases, compare the preclinical and clinical advances, and identify major knowledge gaps and areas of cross-fertilization. We argue that applying paradigms and networks that have proved successful for TB, from basic research to clinical trials, will help to populate the pipeline and accelerate curative regimen development for NTM disease.

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Fig. 1: Timeline and evolution of tuberculosis drug and regimen development concepts.
Fig. 2: Selected anti-mycobacterial drug candidates and their mechanism of action.
Fig. 3: Susceptibility ranges of TB drugs repurposed for the treatment of pulmonary disease caused by nontuberculous mycobacteria, relative to clinical breakpoints.
Fig. 4: Emerging adaptive trial designs for TB.

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Acknowledgements

The authors thank A. Diacon for stimulating discussions on present and future biomarkers of TB drug response. T.D. and V.D. receive support from the National Institute of Allergy and Infectious Diseases of the NIH, Award Numbers R01AI132374 and U19 AI142731, and from the Bill & Melinda Gates Foundation, award number INV-004704, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, NJ, USA

    Véronique Dartois & Thomas Dick

  2. Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, NJ, USA

    Véronique Dartois & Thomas Dick

  3. Department of Microbiology and Immunology, Georgetown University, Washington, DC, USA

    Thomas Dick

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V.D. researched data for the article. Both authors contributed substantially to discussion of the content, wrote the article, and edited and reviewed the manuscript before submission.

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Related links

ClinicalTrials.gov: https://clinicaltrials.gov

MARK-TB: https://www.mark-tb.org/

Risk Stratification Tool for Tuberculosis Clinical Trial Design: http://saviclab.org/tb-risk/

STOP-TB partnership: https://www.stoptb.org/

The Critical Path to TB Drug Regimen: https://c-path.org/programs/cptr/

The European Accelerator of Tuberculosis Regime Project: https://era4tb.org/

The Project to Accelerate New Treatments for Tuberculosis: https://fnih.org/our-programs/project-accelerate-new-treatments-tuberculosis-pan-tb

The TB Drug Accelerator: https://www.tbdrugaccelerator.org/

Working Group on New Drugs: https://www.newtbdrugs.org/

Glossary

Clinical breakpoint

The minimum inhibitory concentration above which an antimicrobial agent is considered to have a low probability of treatment success in the clinic.

Minimum inhibitory concentration (MIC)

The lowest concentration that inhibits bacterial growth in vitro.

Non-inferiority trials

Designed to show that the effect of a new treatment is not worse than that of an active control by more than a specified margin.

Pharmacokinetic–pharmacodynamic (PK–PD)

The relationship between concentrations achieved in the body or in the tissue of interest (PK) and the concentrations required to exert antibacterial effect (PD).

Probability of target attainment (PTA)

PTA analysis evaluates the plasma exposure of an antibiotic in a patient population (pharmacokinetics) against a target exposure required for efficacy and calculates the likelihood of achieving a specific pharmacokinetic–pharmacodynamic criterion (‘target′) expressed relative to the minimum inhibitory concentration for a pathogen in that patient population.

Sputum culture conversion

Conversion of sputum from which Mycobacterium tuberculosis 9MTB0 can be grown under standardized condition to sputum from which no M. tuberculosis can be cultured. This conversion from positive to negative is the best way to determine whether a patient is responding to treatment. Spontaneous conversion was seen in a fraction of patients during the pre-antibiotic era.

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Dartois, V., Dick, T. Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease. Nat Rev Drug Discov (2024). https://doi.org/10.1038/s41573-024-00897-5

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