2. Academic Validation
  3. Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis

Proapoptotic Bcl-2 inhibitor as potential host directed therapy for pulmonary tuberculosis

  • Nat Commun. 2025 Mar 27;16(1):3003. doi: 10.1038/s41467-025-58190-x.
Medha Singh 1 2 3,  Mona O Sarhan 1 2 3,  Nerketa N L Damiba 1 2,  Alok K Singh 1 2 3 4,  Andres Villabona-Rueda 5,  Oscar J Nino-Meza 1 2 3,  Xueyi Chen 1 2 3,  Yuderleys Masias-Leon 1 2 3,  Carlos E Ruiz-Gonzalez 1 2 3,  Alvaro A Ordonez 1 2 3,  Franco R D'Alessio 5,  Eric O Aboagye 6,  Laurence S Carroll 7,  Sanjay K Jain 8 9 10 11
Affiliations

Affiliations

  • 1 Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 2 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 3 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 4 Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India.
  • 5 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 6 Comprehensive Cancer Imaging Centre, Department of Surgery & Cancer, Hammersmith Campus, Imperial College, London, UK.
  • 7 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 8 Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu.
  • 9 Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu.
  • 10 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu.
  • 11 Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhmi.edu.
PMID: 40148277 DOI: 10.1038/s41467-025-58190-x
Abstract

Mycobacterium tuberculosis establishes within host cells by inducing anti-apoptotic Bcl-2 Family proteins, triggering necrosis, inflammation, and fibrosis. Here, we demonstrate that navitoclax, an orally bioavailable, small-molecule Bcl-2 Inhibitor, significantly improves pulmonary tuberculosis (TB) treatments as a host-directed therapy. Addition of navitoclax to standard TB treatments at human equipotent dosing in mouse models of TB, inhibits Bcl-2 expression, leading to improved Bacterial clearance, reduced tissue necrosis, fibrosis and decreased extrapulmonary Bacterial dissemination. Using immunohistochemistry and flow cytometry, we show that navitoclax induces Apoptosis in several immune cells, including CD68+ and CD11b+ cells. Finally, positron emission tomography (PET) in live Animals using clinically translatable biomarkers for Apoptosis (18F-ICMT-11) and fibrosis (18F-FAPI-74), demonstrates that navitoclax significantly increases Apoptosis and reduces fibrosis in pulmonary tissues, which are confirmed in postmortem analysis. Our studies suggest that proapoptotic drugs such as navitoclax can potentially improve pulmonary TB treatments, reduce lung damage / fibrosis and may be protective against post-TB lung disease.

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