L-Serine and Palmitoyl CoA control Mycobacterial infection by tweaking protective immune response: A potential host directed therapy for tuberculosis

Host-directed therapies (HDTs) have acquired paramount importance for management of tuberculosis (TB). L-Serine is an important metabolite and immunomodulatory biomolecule with promising role in managing infections, and autoimmune diseases. However, the role of L-Serine as host directed therapeutic against Mycobacterium tuberculosis ( M.tb ) remains unexplored. Therefore, we adopted de novo -based approach and employed L-Serine and palmitoyl CoA precursors for enhancing sphingolipid in host and accessed their anti-tubercular potential. In this study, we investigated whether L-Serine could modulate the antibiotics efficacy against M.tb . L-Serine particularly in combination with palmitic acid, rifampicin and isoniazid showed enhanced intracellular bacterial clearance in a dose- and time-dependent manner in murine and human macrophages. This synergistic effect was accompanied by increased nitric oxide production and modulation of the host immune response. We identified elevated levels of pro-inflammatory cytokine TNF-α and reduced anti-inflammatory IL-10 expression. Furthermore, L-Serine supplementation demonstrated antimicrobial activity in isolated primary CD14⁺ monocytes from TB patients. Similarly, the metabolic supplementation of L-Serine in combination with isoniazid, rifampicin, and palmitic acid significantly reduced bacterial burden in the lungs and spleen, while improving tissue architecture in murine infection model. Our observations suggest that L-Serine and palmitic acid in combination with isoniazid and rifampicin contributes to the observed therapeutic effects. Collectively, this study concludes that L-Serine and palmitic acid acts as a promising host-directed therapeutic adjunct, which enhances antimicrobial immunity and potentiating antibiotic efficacy, providing a potential strategy for improving tuberculosis treatment outcomes.