An adenylyl cyclase switch reroutes carbon from growth to virulence lipids in Mycobacterium tuberculosis
- 1Institute for Systems Biology, Seattle, WA 98109, USA
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.
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BibTeX
@misc{immanuel2026adenylyl,
title = {{An adenylyl cyclase switch reroutes carbon from growth to virulence lipids in Mycobacterium tuberculosis}},
author = {S. R. C. Immanuel and J. Do and E. J. R. Peterson and K. A. Hunt and A. Kaur and M. Pan and A. Singh and W.-J. Wu and A. Bhatt and N. S. Baliga},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.750769},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.750769v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - An adenylyl cyclase switch reroutes carbon from growth to virulence lipids in Mycobacterium tuberculosis
AU - S. R. C. Immanuel
AU - J. Do
AU - E. J. R. Peterson
AU - K. A. Hunt
AU - A. Kaur
AU - M. Pan
AU - A. Singh
AU - W.-J. Wu
AU - A. Bhatt
AU - N. S. Baliga
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.750769
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.750769v1
AB - 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.
ER -