Repurposing benztropine as TB host directed therapy

With an estimated 1.6 million annual deaths, tuberculosis (TB) remains the major cause for bacterial mortality worldwide (1). Despite significant success in reducing mortality over the past few decades, fully controlling TB with existing antibiotics remains a considerable challenge. Current treatment for TB involves a combination of at least 3 different antibiotics that directly target the causative agent of TB, Mycobacterium tuberculosis (Mtb). Major shortcomings of current TB drugs include (i) failure to shorten treatment duration and (ii) poor efficacy against multi drug resistant (MDR) Mtb. To overcome these challenges, new therapies with novel modes of action are sought, amongst which host-directed therapeutics (HDTs) are considered a novel and attractive approach (2–4).

A focused single dose screening of the COVID box library identified the Parkinson’s drug benztropine as active against intracellular Mycobacterium tuberculosis H37Rv (Mtb). Benztropine exhibited a dose dependent growth inhibition, at μM concentrations, against intracellular Mtb, Mycobacterium bovis (BCG) and Salmonella typhimurium with no direct antibacterial activity in broth media. A combination of pharmacological and RNA interference and CRISPR knock out technologies were used to determine benztropine mode of action revealing that benztropine exerts its intracellular anti-microbial activity through the macrophage histamine receptor 1 (H1). Furthermore, we show that histamine promotes intracellular Mtb growth in macrophages through H1 receptor activation. Altogether, our findings suggest the potential of benztropine to be repurposed against tuberculosis (TB) and may also pave the way for development of a new host-directed anti-infective intracellular drug class that targets H1 in infected macrophages.

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Publisher: REPO4EU

Publication date (Electronic, pub): 12 September 2023

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[1 ] Departments of Medicine and Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, B.C. (Canada) ( https://ror.org/03rmrcq20)

Article

DOI: 10.58647/REXPO.23006

SO-VID: 5ac54a36-0014-4931-89e8-2ca4b5c22673

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Published under Creative Commons Attribution 4.0 International ( CC BY 4.0). Users are allowed to share (copy and redistribute the material in any medium or format) and adapt (remix, transform, and build upon the material for any purpose, even commercially), as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source.

Conference name: RExPO23

Conference number: 2

Conference location: Stockholm, Sweden

Conference date: 25-26 October 2023

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References

Chakaya Jeremiah, Petersen Eskild, Nantanda Rebecca, Mungai Brenda N., Migliori Giovanni Battista, Amanullah Farhana, Lungu Patrick, Ntoumi Francine, Kumarasamy Nagalingeswaran, Maeurer Markus, Zumla Alimuddin. The WHO Global Tuberculosis 2021 Report – not so good news and turning the tide back to End TB. International Journal of Infectious Diseases. Vol. 124:2022. Elsevier BV. [Cross Ref]
Kilinç Gül, Saris Anno, Ottenhoff Tom H. M., Haks Mariëlle C.. Host‐directed therapy to combat mycobacterial infections*. Immunological Reviews. Vol. 301(1):62–83. 2021. Wiley. [Cross Ref]
Baindara Piyush. Host-directed therapies to combat tuberculosis and associated non-communicable diseases. Microbial Pathogenesis. Vol. 130:156–168. 2019. Elsevier BV. [Cross Ref]
Ahmed Sultan, Raqib Rubhana, Guðmundsson Guðmundur Hrafn, Bergman Peter, Agerberth Birgitta, Rekha Rokeya Sultana. Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation. Antibiotics. Vol. 9(1)2020. MDPI AG. [Cross Ref]

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[1] Chakaya Jeremiah, Petersen Eskild, Nantanda Rebecca, Mungai Brenda N., Migliori Giovanni Battista, Amanullah Farhana, Lungu Patrick, Ntoumi Francine, Kumarasamy Nagalingeswaran, Maeurer Markus, Zumla Alimuddin. The WHO Global Tuberculosis 2021 Report – not so good news and turning the tide back to End TB. International Journal of Infectious Diseases. Vol. 124:2022. Elsevier BV. [Cross Ref]

[2] Kilinç Gül, Saris Anno, Ottenhoff Tom H. M., Haks Mariëlle C.. Host‐directed therapy to combat mycobacterial infections*. Immunological Reviews. Vol. 301(1):62–83. 2021. Wiley. [Cross Ref]

[3] Baindara Piyush. Host-directed therapies to combat tuberculosis and associated non-communicable diseases. Microbial Pathogenesis. Vol. 130:156–168. 2019. Elsevier BV. [Cross Ref]

[4] Ahmed Sultan, Raqib Rubhana, Guðmundsson Guðmundur Hrafn, Bergman Peter, Agerberth Birgitta, Rekha Rokeya Sultana. Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation. Antibiotics. Vol. 9(1)2020. MDPI AG. [Cross Ref]