MYCOBACTERIAL DORMANCY AND PERSISTENCE: MOLECULAR MECHANISMS CONTROLLING STRESS RESPONSE, SURVIVAL AND ADAPTATION

Abstract

Though tuberculosis is among the most common diseases worldwide, growing antibiotic resistance and a weak drug development pipeline motivate discovery of new pathophysiological mechanisms underlying mycobacterial infections. A distinguishing feature of mycobacterial pathogens is their ability to adapt to the stresses of infection, such as nutrient deprivation and hypoxia, by entering a non-replicating, antibiotic-tolerant state. We used data-driven, systems biology platforms to characterize adaptive networks underlying the stress response in mycobacteria and found that starved mycobacteria enter a state of lipid metabolism-induced ketosis mediated by cytochrome P450s; targeted killing of persisters was accomplished using Fenton reactions that damaged these enzymes. Hypoxia induced biochemical reprogramming of tRNAs ribonucleosides which enabled selective translation of codon-biased mRNAs essential to survival. Disruption of this system resulted in mistimed dormancy responses killing the bacteria. Together, these discoveries offer molecular insights into mycobacterial stress responses, providing new targets for tuberculosis diagnosis, management and treatment.