Induction of oxidative stress Mycobacterium bovis BCG-pfurA-RFP ATCC 35734 assessed as activation of pfurA at 0.5 to 2 times MIC90 after 24 hrs by fluorescence assay
- Deposit:2022-08-30
- Modify:2024-05-03
Title: Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against Mycobacterium tuberculosis.
Abstract: Disruption of redox homeostasis in mycobacteria causes irreversible stress induction and cell death. Here, we report the dioxonaphthoimidazolium scaffold as a novel redox cycling antituberculosis chemotype with potent bactericidal activity against growing and nutrient-starved phenotypically drug-resistant nongrowing bacteria. Maximal potency was dependent on the activation of the redox cycling quinone by the positively charged scaffold and accessibility to the mycobacterial cell membrane as directed by the lipophilicity and conformational characteristics of the N-substituted side chains. Evidence from microbiological, biochemical, and genetic investigations implicates a redox-driven mode of action that is reliant on the reduction of the quinone by type II NADH dehydrogenase (NDH2) for the generation of bactericidal levels of the reactive oxygen species (ROS). The bactericidal profile of a potent water-soluble analogue 32 revealed good activity against nutrient-starved organisms in the Loebel model of dormancy, low spontaneous resistance mutation frequency, and synergy with isoniazid in the checkerboard assay.
Journal: J Med Chem
Year: 2021
Volume: 64
Issue: 21.0
First Page: 15991
Last Page: 16007
DOI: 10.1021/acs.jmedchem.1c01383
Target ChEMBL ID: CHEMBL615052
ChEMBL Target Name: Mycobacterium tuberculosis variant bovis BCG
ChEMBL Target Type: ORGANISM - Target is a complete organism
Relationship Type: N - Non-molecular target assigned
Confidence: Target assigned is non-molecular
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