Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India; Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
Reshma T Veetil
National Centre for Biological Sciences, Bangalore, India
Karthikeyan Mohanraj
The Institute of Mathematical Sciences, A CI of Homi Bhabha National Institute, Chennai, India
Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India; Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
National Centre for Biological Sciences, Bangalore, India
Devleena Bandopadhyay
Molecular Biophysics Unit, Indian Institute of Science Bangalore, Bangalore, India
Hussain Beig
Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India; Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
Shalini Birua
Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India; Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
Shreyas Niphadkar
Institute for Stem Cell Science and Regenerative Medicine, Bangalore, India
Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India; Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
Vikrant Kumar Sinha
Molecular Biophysics Unit, Indian Institute of Science Bangalore, Bangalore, India
Chandrani Thakur
Department of Biochemistry, Indian Institute of Science Bangalore, Bangalore, India
Raju S Rajmani
Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India; Centre for Infectious Disease Research, Indian Institute of Science Bangalore, Karnataka, India
Mycobacterium tuberculosis (Mtb) is evolutionarily equipped to resist exogenous reactive oxygen species (ROS) but shows vulnerability to an increase in endogenous ROS (eROS). Since eROS is an unavoidable consequence of aerobic metabolism, understanding how Mtb manages eROS levels is essential yet needs to be characterized. By combining the Mrx1-roGFP2 redox biosensor with transposon mutagenesis, we identified 368 genes (redoxosome) responsible for maintaining homeostatic levels of eROS in Mtb. Integrating redoxosome with a global network of transcriptional regulators revealed a hypothetical protein (Rv0158) as a critical node managing eROS in Mtb. Disruption of rv0158 (rv0158 KO) impaired growth, redox balance, respiration, and metabolism of Mtb on glucose but not on fatty acids. Importantly, rv0158 KO exhibited enhanced growth on propionate, and the Rv0158 protein directly binds to methylmalonyl-CoA, a key intermediate in propionate catabolism. Metabolite profiling, ChIP-Seq, and gene-expression analyses indicate that Rv0158 manages metabolic neutralization of propionate toxicity by regulating the methylcitrate cycle. Disruption of rv0158 enhanced the sensitivity of Mtb to oxidative stress, nitric oxide, and anti-TB drugs. Lastly, rv0158 KO showed poor survival in macrophages and persistence defect in mice. Our results suggest that Rv0158 is a metabolic integrator for carbon metabolism and redox balance in Mtb.