An adenylyl cyclase switch reroutes carbon from growth to virulence lipids in Mycobacterium tuberculosis

Authors

Immanuel, S. R. C., Do, J., Peterson, E. J. R., Hunt, K. A., Kaur, A., Pan, M., Singh, A., Wu, W.-J., Bhatt, A., Baliga, N. S.

Abstract

Anti-TB drugs act non-uniformly on Mycobacterium tuberculosis (Mtb) because of its distinct physiological states across diverse infection niches shaped by host-derived nutrients and stresses. Agonists of the adenylyl cyclase Rv1625c are a novel drug class that selectively inhibits Mtb growth in macrophages and cholesterol-rich conditions by an unknown mechanism. Combining condition-resolved transcriptomics, genome-scale metabolic modeling, and genetic perturbation, we show these agonists cause a blockade in the electron transport chain, which likely activates Rv1625c. The elevated cAMP in turn drives global transcriptional and post-translational remodeling of central carbon and lipid metabolism. The resulting methylcitrate cycle reversal chokes cholesterol breakdown products from entering central metabolism, diverting carbon toward cell wall and virulence-lipid (phthiocerol dimycocerosate) synthesis and inhibiting growth. These drugs thus hijack an endogenous switch that reroutes carbon from biomass to virulence-lipid production. Hence, nutrients that restore carbon flux and relieve ETC blockade reduce activity, whereas Rv1625c overexpression and ETC inhibitors potentiate drug action even in refractory conditions.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 17 Sep 2026.

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