CRISPR interference identifies vulnerable cellular pathways with bactericidal phenotypes in Mycobacterium tuberculosis.

Autor: McNeil MB; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand., Keighley LM; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand., Cook JR; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand., Cheung CY; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand., Cook GM; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
Jazyk: angličtina
Zdroj: Molecular microbiology [Mol Microbiol] 2021 Oct; Vol. 116 (4), pp. 1033-1043. Date of Electronic Publication: 2021 Aug 21.
DOI: 10.1111/mmi.14790
Abstrakt: Mycobacterium tuberculosis remains a leading cause of death for which new drugs are needed. The identification of drug targets has been advanced by high-throughput and targeted genetic deletion strategies. Each though has limitations including the inability to distinguish between levels of vulnerability, lethality, and scalability as a molecular tool. Using mycobacterial CRISPR interference in combination with phenotypic screening, we have overcome these individual issues to investigate essentiality, vulnerability and lethality for 94 target genes from a diverse array of cellular pathways, many of which are potential antibiotic targets. Essential genes involved in cell wall synthesis and central cellular functions were equally vulnerable and often had bactericidal consequences. Conversely, essential genes involved in metabolism, oxidative phosphorylation, or amino acid synthesis were less vulnerable to inhibition and frequently bacteriostatic. In conclusion, this study provides novel insights into mycobacterial genetics and biology that will help to prioritize potential drug targets.
(© 2021 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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