Arginine-deprivation–induced oxidative damage sterilizes Mycobacterium tuberculosis

Significance Tuberculosis results in over 1.7 million deaths annually; this problem is worsened by the emergence of drug-resistant strains. New drugs and a better understanding of the mechanisms of existing interventions are needed to prevent the development of drug resistance. Reactive oxygen species (ROS)-mediated lethality by bactericidal drugs was observed inMycobacterium tuberculosis (Mtb ). Our studies demonstrate that arginine deprivation sterilizes forMtb in vitro and in the host. Using several complementary approaches, we show that arginine deprivation leads to the depletion of thiols, accumulation of ROS, DNA damage, and rapidMtb death. We propose enzymes in the de novo arginine biosynthesis pathway represent promising drug target candidates to be inhibited to treatMtb and its drug-resistant strains.