KatG inactivation generates vulnerabilities in isoniazid resistant strains ofMycobacterium tuberculosis

Abstract

AbstractDrug-resistant strains ofMycobacterium tuberculosisare a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in thekatGencoded bifunctional catalase-peroxidase. We hypothesised that perturbed KatG activity would generate collateral vulnerabilities in INH-resistantkatGmutants, providing new pathways to combat isoniazid resistance. Here, we used whole genome CRISPRi screens, transcriptomics, and metabolomics to generate a genome-wide map of cellular vulnerabilities in aM. tuberculosis katGmutant. We discovered that metabolic and transcriptional remodelling compensates for the loss of KatG but in doing so generates vulnerabilities in ribosome biogenesis, and nucleotide and amino acid metabolism. These vulnerabilities were more sensitive to inhibition in an isoniazid-resistantkatGmutant underin vitroand host-relevant conditions and translated to clinical populations. These findings provide an experimental framework for developing novel strategies to combat antimicrobial resistance inM. tuberculosisand other bacterial pathogens.