Functionalized Dioxonaphthoimidazoliums: A Redox Cycling Chemotype with Potent Bactericidal Activities against Mycobacterium tuberculosis

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.