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

Medha Singh, Mona O. Sarhan, Nerketa N. L. Damiba, Alok K. Singh, Andres Villabona-Rueda, Oscar J. Nino-Meza, Xueyi Chen, Yuderleys Masias-Leon, Carlos E. Ruiz-Gonzalez, Alvaro A. Ordonez, Franco R. D’Alessio, Eric O. Aboagye, Laurence S. Carroll and Sanjay K. Jain ()
Additional contact information
Medha Singh: Johns Hopkins University School of Medicine
Mona O. Sarhan: Johns Hopkins University School of Medicine
Nerketa N. L. Damiba: Johns Hopkins University School of Medicine
Alok K. Singh: Johns Hopkins University School of Medicine
Andres Villabona-Rueda: Johns Hopkins University School of Medicine
Oscar J. Nino-Meza: Johns Hopkins University School of Medicine
Xueyi Chen: Johns Hopkins University School of Medicine
Yuderleys Masias-Leon: Johns Hopkins University School of Medicine
Carlos E. Ruiz-Gonzalez: Johns Hopkins University School of Medicine
Alvaro A. Ordonez: Johns Hopkins University School of Medicine
Franco R. D’Alessio: Johns Hopkins University School of Medicine
Eric O. Aboagye: Imperial College
Laurence S. Carroll: Johns Hopkins University School of Medicine
Sanjay K. Jain: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-58190-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58190-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-58190-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().