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bioRxiv · 10.64898/2026.08.20.745965

L-Serine potentiates the efficacy of Isoniazid, and Rifampicin as host-directed adjunctive treatment for Mycobacterium tuberculosis.

Sharma, N.·Sharma, R.·Kumar, A.·Singh, L. K.·Ayanur, A.·Hadda, V.·Singh, A. K.·Prakash, H.
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Abstract

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- 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.

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Sharma, N., Sharma, R., Kumar, A., Singh, L. K., Ayanur, A., Hadda, V., Singh, A. K., Prakash, H.. 2026-08-21. L-Serine potentiates the efficacy of Isoniazid, and Rifampicin as host-directed adjunctive treatment for Mycobacterium tuberculosis.. https://doi.org/10.64898/2026.08.20.745965

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