CRISPR Screening and Comparative LC-MS Analysis Identify Genes Mediating Efficacy of Delamanid and Pretomanid against Mycobacterium tuberculosis.

ABSTRACT: Tuberculosis (TB), the leading cause of death from bacterial infections worldwide, results from infection with Mycobacterium tuberculosis (Mtb). The antitubercular agents delamanid (DLM) and pretomanid (PMD) are nitroimidazole prodrugs that require activation by an enzyme intrinsic to Mtb; however, the mechanism(s) of action and the associated metabolic pathways are largely unclear. Profiling of the chemical-genetic interactions of PMD and DLM in Mtb using combined CRISPR screening reveals that the mutation of rv2073c increases susceptibility of Mtb to these nitroimidazole drugs both in vitro and in infected mice, whereas mutation of rv0078 increases drug resistance. Further assays show that Rv2073c might confer intrinsic resistance to DLM/PMD by interfering with inhibition of the drug tar

SUBMITTER: Yan MY 

PROVIDER: S-EPMC11497083 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature