Design, Synthesis, and Efficacy Testing of Nitroethylene- and 7‑Nitrobenzoxadiazol-Based Flavodoxin Inhibitors against Helicobacter pylori Drug-Resistant Clinical Strains and in Helicobacter pylori-Infected Mice

Helicobacter pylori (Hp) infection is the main cause of peptic ulcer
and gastric cancer. Hp eradication rates have fallen
due to increasing bacterial
resistance to currently used broad-spectrum antimicrobials. We have
designed, synthesized, and tested redox variants of nitroethylene-
and 7-nitrobenzoxadiazole-based inhibitors of the essential Hp protein flavodoxin. Derivatives of the 7-nitrobenzoxadiazole
lead, carrying reduced forms of the nitro group and/or oxidized forms
of a sulfur atom, display high therapeutic indexes against several
reference Hp strains. These inhibitors are effective
against metronidazole-, clarithromycin-, and rifampicin-resistant Hp clinical isolates. Their toxicity for mice after oral
administration is low, and, when administered individually at single
daily doses for 8 days in a mice model of Hp infection,
they decrease significantly Hp gastric colonization
rates and are able to eradicate the infection in up to 60% of the
mice. These flavodoxin inhibitors constitute a novel family of Hp-specific antimicrobials that may help fight the constant
increase of Hp antimicrobial-resistant strains.