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

Mycobacterium tuberculosis, the bacterium responsible for tuberculosis, employs distinct physiological states in various infection niches influenced by host-derived nutrients and stresses. A novel class of anti-TB drugs, which target adenylyl cyclase Rv1625c, selectively inhibit Mtb growth in macrophages and cholesterol-rich environments through an unknown mechanism.

Through a combination of condition-resolved transcriptomics, genome-scale metabolic modeling, and genetic perturbation, researchers have discovered that these drugs cause a blockade in the electron transport chain, subsequently activating Rv1625c. The subsequent increase in cAMP triggers global transcriptional and post-translational remodeling of central carbon and lipid metabolism.

The methylcitrate cycle is reversed, preventing cholesterol breakdown products from entering the central metabolism and instead diverting carbon towards cell wall and virulence-lipid (phthiocerol dimycocerosate) synthesis, thus inhibiting growth. Consequently, these drugs exploit an endogenous switch in Mtb that reroutes carbon from biomass synthesis to virulence-lipid production.

Therefore, nutrients that restore carbon flux and alleviate the electron transport chain blockade diminish drug activity, whereas overexpression of Rv1625c and electron transport chain inhibitors enhance drug efficacy, even in refractory conditions.