Metabolic perturbation reduces antibiotic tolerance in Mycobacterium tuberculosis

Mycobacterium tuberculosis is tolerant to many antibiotics, leading to impaired antibiotic killing. Using CRISPR interference (CRISPRi) transcriptional knockdowns, we generated a panel of metabolically compromised strains to identify tolerance pathways for pursuing in therapeutic development. Disrupting the regulation of intracellular iron storage, amino acid biosynthesis and redox defence mechanisms potentiated the lethality of multiple drugs and translated to infected THP-1 macrophages. This work reinforces the role of metabolism as a major contributor to drug tolerance in M. tuberculosis.