Anti-Tuberculosis Drug Development and Evaluation in Animal Models

Tuberculosis remains a leading cause of infectious morbidity and mortality worldwide, compounded by the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis. Novel therapeutic candidates must be assessed not only for potent in vitro activity but also for favourable pharmacokinetics, lesion penetration and sterilising capacity in animal hosts. A diverse array of models—from standard mouse strains and immunocompromised or humanised rodents to guinea pigs and rabbits—has been developed to recapitulate key aspects of human pulmonary pathology, including caseous necrosis, cavitation and heterogeneous granuloma formation. These systems facilitate the evaluation of drug distribution at sites of infection, the impact of host immune microenvironments on bacterial replication, and the capacity of regimens to prevent relapse. Recent advances in translational pharmacokinetic-pharmacodynamic frameworks, physiologically based pharmacokinetic modelling and high-resolution imaging have improved the predictivity of preclinical findings for clinical outcomes. Collectively, these approaches underpin the rational optimisation of dosing, the design of combination regimens and the identification of correlates of sterilising activity, thereby accelerating the pipeline for new anti-tuberculosis therapies with global impact.

Research from Nature Portfolio

One of the most significant recent strides involves optimisation of an oxazolidinone candidate within a three-drug regimen for drug-resistant tuberculosis. Using a translational modelling platform that integrates preclinical monotherapy, combination therapy and lesion-penetration data with emerging human phase I results, researchers have defined dosing ranges predicted to achieve rapid culture conversion in over 90% of patients by two months. This work has refined dose selection for late-stage regimens combining the novel oxazolidinone with bedaquiline and pretomanid, thereby supporting seamless progression from animal studies to proof-of-concept trials.

Anti-Tuberculosis Drug Development and Evaluation in Animal Models publication trend

The graph below shows the total number of articles in anti-tuberculosis drug development and evaluation in animal models across all publications each year (not limited to Nature Index journals).

Technical terms

Granuloma: A structured aggregate of immune cells formed in response to M. tuberculosis, often featuring a necrotic core.

Caseous necrosis: Central cell death within granulomas, yielding a cheese-like lesion environment that impedes drug penetration.

Physiologically based pharmacokinetic (PBPK) model: A mechanistic mathematical model describing absorption, distribution, metabolism and excretion of drugs across organ systems.

Translational framework: An integrative approach that combines animal and early human data to predict clinical outcomes and optimise dosing.

Culture conversion: The transition from positive to negative bacterial cultures in sputum or tissue, indicating effective sterilisation.

References

1. Discovery of natural-product-derived sequanamycins as potent oral anti-tuberculosis agents. Cell (2023).
2. Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen. Nature Communications (2024).
3. Development of a Minimalistic Physiologically Based Pharmacokinetic (mPBPK) Model for the Preclinical Development of Spectinamide Antibiotics. Pharmaceutics (2023).
4. Contribution of Pretomanid to Novel Regimens Containing Bedaquiline with either Linezolid or Moxifloxacin and Pyrazinamide in Murine Models of Tuberculosis. Antimicrobial Agents and Chemotherapy (2019).