Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis

• DOI: 10.1038/s41467-024-54072-w
• Publication Date: 2024-11-13T10:47:33Z
• Authors: XinYue Wang; William J. Jowsey; Chen-Yi Cheung; Caitlan J. Smart; Hannah R. Klaus; Noon EJ Seeto; Natalie JE Waller; Michael T. Chrisp; Amanda L. Peterson; Boatema Ofori-Any...; Emily Strong; Brunda Nijagal; Nicholas P. West; Jason H. Yang; Peter C. Fineran; Gregory M. Cook; Simon A. Jackson; Matthew B. McNeil
• Keywords: Druggability

Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities isoniazid-resistant katG mutants, providing potential pathway targets combat resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used genome-wide map cellular an mutant strain M. tuberculosis. Here, we show metabolic transcriptional remodelling compensates for loss but doing so generates respiration, ribosome biogenesis, nucleotide amino acid metabolism. Importantly, these more sensitive inhibition translated clinical isolates. This work highlights how changes physiology drug-resistant druggable can be exploited improve outcomes.