A PARKINSON’S disease medication has demonstrated potent activity against Mycobacterium tuberculosis through a novel host-directed mechanism, offering a potential new avenue for combating the disease and addressing antimicrobial resistance.
Researchers identified benztropine as an effective inhibitor of intracellular M. tuberculosis using high-content screening. The drug was active in both human and murine macrophages but showed no effect in broth culture, indicating its mechanism depends on the host cell environment. In a mouse model of aerosol M. tuberculosis infection, oral administration of benztropine reduced lung bacterial burden by up to 70%.
Beyond tuberculosis, benztropine was also active against Salmonella enterica serovar Typhimurium in an abscess infection model, significantly decreasing lesion size and bacterial counts. Detailed mechanistic studies, including chemical competition assays, CRISPR knockouts, and siRNA silencing, revealed that the drug’s antimicrobial effect is mediated through macrophage histamine receptor 1 (HRH1). This HRH1-dependent action underscores a targeted host-cell pathway rather than direct antibacterial activity.
Host-directed therapies such as this may complement or enhance traditional antimicrobial regimens, potentially reducing the emergence of resistance by targeting host mechanisms rather than the bacteria directly. The findings position benztropine as a promising repurposing candidate and a lead compound for the development of HRH1-targeting antibacterial agents. While further research will be necessary to evaluate safety, efficacy, and potential integration into treatment protocols for human patients, the results mark an encouraging step toward innovative tuberculosis control strategies.
Reference:
Sahile HA et al. The Parkinson’s drug benztropine possesses histamine receptor 1-dependent host-directed antimicrobial activity against Mycobacterium tuberculosis. npj Antimicrob Resist. 2025;3:70.
