Metabolic rewiring of isoniazid sensitivity in Mycobacterium tuberculosis
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wang-et-al-2025-metabolic-rewiring-of-isoniazid-sensitivity-in-mycobacterium-tuberculosis.pdf
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9.16 MB
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Author(s)
Wang, Erin
Cho, Ke
Harrison, Gregory
Smelyansky, Stephanie
Soni, Vijay
Smirn, Asya
Mckee, Samuel
Ghabrial, George
Flent, Kelly
Beatty, Wandy
Date Issued
September 2, 2025
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
E.R. Wang, K. Cho, G.A. Harrison, S.R. Smelyansky, V. Soni, A. Smirnov, S.R. McKee, G.S. Ghabrial, K.N. Flentie, W. Beatty, B. Ofori-Anyinam, S. Sarkar, T. Hurtaux, L. Loza, F. Almqvist, T.L. Doering, J.H. Yang, L.L. Kiessling, K.Y. Rhee, G.J. Patti, & C.L. Stallings, Metabolic rewiring of isoniazid sensitivity in Mycobacterium tuberculosis, Proc. Natl. Acad. Sci. U.S.A. 122 (36) e2421336122 (2025).
Version
Final published version
Abstract
Significance Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent. The frontline antibiotic isoniazid (INH), which inhibits mycolic acid biosynthesis in Mtb , is at the cornerstone of all current regimens to treat drug-sensitive Mtb infection. However, over 10% of Mtb infections are resistant to INH. We have found that rerouting metabolic flux in an INH-resistant Mtb strain is associated with sensitization of the bacteria to INH-mediated killing independent of mycolic acid synthesis, revealing a previously unappreciated mechanism of action for INH and a new strategy to improve the efficacy of INH when treating drug-susceptible and drug-resistant tuberculosis.
Subjects
Author contributions: E.R.W., K.C., G.A.H., S.R.S., K.N.F., G.J.P., and C.L.S. designed research
E.R.W., K.C., G.A.H., S.R.S., A.S., S.R.M., G.S.G., K.N.F., W.B., B.O.-A., T.H., and L.L. performed research
E.R.W., K.C., G.A.H., S.R.S., V.S., K.N.F., W.B., B.O.-A., S.S., T.H., L.L., F.A., T.L.D., J.H.Y., L.L.K., K.Y.R., and G.J.P. contributed new reagents/ analytic tools
E.R.W., K.C., G.A.H., S.R.S., A.S., S.R.M., G.S.G., K.N.F., W.B., B.O.-A., T.H., L.L., T.L.D., J.H.Y., L.L.K., K.Y.R., G.J.P., and C.L.S. analyzed data
and E.R.W. and C.L.S. wrote the paper
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Ragon Institute of MGH, MIT and Harvard
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1073/pnas.2421336122
