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

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-Anyinam, Emily Strong, Brunda Nijagal, Nicholas P. West, Jason H. Yang, Peter C. Fineran, Gregory M. Cook, Simon A. Jackson and Matthew B. McNeil ()
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XinYue Wang: University of Otago
William J. Jowsey: University of Otago
Chen-Yi Cheung: University of Otago
Caitlan J. Smart: University of Otago
Hannah R. Klaus: University of Otago
Noon EJ Seeto: University of Otago
Natalie JE Waller: University of Otago
Michael T. Chrisp: University of Otago
Amanda L. Peterson: The University of Melbourne
Boatema Ofori-Anyinam: Rutgers New Jersey Medical School
Emily Strong: The University of Queensland
Brunda Nijagal: The University of Melbourne
Nicholas P. West: The University of Queensland
Jason H. Yang: Rutgers New Jersey Medical School
Peter C. Fineran: University of Otago
Gregory M. Cook: University of Otago
Simon A. Jackson: University of Otago
Matthew B. McNeil: University of Otago

Nature Communications, 2024, vol. 15, issue 1, 1-18

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

Date: 2024
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DOI: 10.1038/s41467-024-54072-w

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