Upon inhibition of respiration, which occurs in hypoxic or nitric oxide-containing host microenvironments, Mycobacterium tuberculosis (Mtb) adopts a non-replicating ‘quiescent’ state and becomes relatively unresponsive to antibiotic treatment. Using a combination of metabolite profiling and comprehensive mutant fitness analysis we are identfying regulatory and metabolic pathways that can be targeted to kill quiescent Mtb. Based on these studies, we propose a multi-step pathway that is responsible for growth arrest, metabolic remodeling, and antibiotic tolerance under hypoxic conditions. Cyclic AMP (cAMP) plays a central role in this process through the activation of a cAMP-activated protein lysine acetyl-transferase, which coordinately regulates fatty acid catabolism and oxidative TCA reactions to maintain the redox state of the NAD+/NADH pool. The result of this metabolic remodeling is preferential carbon flux through reductive TCA reactions that depend on malate dehydrogenase (MDH) activity. Genetic and chemical inhibition of MDH resulted in rapid cell death in both hypoxic cultures and in murine lung, suggesting a new strategy for eradicating quiescent bacteria.