Host‐directed anti‐mycobacterial activity of colchicine, an anti‐gout drug, via strengthened host innate resistance reinforced by the IL‐1β/PGE2 axis.

Background and Purpose: To diversify and expand possible tuberculosis (TB) drug candidates and maximize limited global resources, we investigated the effect of colchicine, an FDA‐approved anti‐gout drug, against Mycobacterium tuberculosis (Mtb) infection because of its immune‐modulating effects. Experimental Approach: We evaluated the intracellular anti‐Mtb activity of different concentrations of colchicine in murine bone marrow‐derived macrophages (BMDMs). To elucidate the underlying mechanism, RNA sequencing, biological and chemical inhibition assays, and Western blot, quantitative real‐time PCR, enzyme‐linked immunosorbent assay (ELISA), and immunohistochemical analyses were employed. Finally, type I interferon‐dependent highly TB‐susceptible A/J mice were challenged with virulent Mtb H37Rv, and the host‐directed therapeutic effect of oral colchicine administration on bacterial burdens and lung inflammation was assessed 30 days post‐infection (2.5 mg·kg−1 every 2 days). Key Results: Colchicine reinforced the anti‐Mtb activity of BMDMs without affecting cell viability, indicating that colchicine facilitated macrophage immune activation upon Mtb infection. The results from RNA sequencing, NLRP3 knockout BMDM, IL‐1 receptor blockade, and immunohistochemistry analyses revealed that this unexpected intracellular anti‐Mtb activity of colchicine was mediated through NLRP3‐dependent IL‐1β signalling and Cox‐2‐regulated PGE2 production in macrophages. Consequently, the TB‐susceptible A/J mouse model showed remarkable protection, with decreased bacterial loads in both the lungs and spleens of oral colchicine‐treated mice, with significantly elevated Cox‐2 expression at infection sites. Conclusions and Implications: The repurposing of colchicine against Mtb infection in this study highlights its unique function in macrophages upon Mtb infection and its novel potential use in treating TB as host‐directed or adjunctive therapy. [ABSTRACT FROM AUTHOR]