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

Helicobacter pylori(Hp) infection is the main cause of peptic ulcer and gastric cancer. Hperadication 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 Hpprotein 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 Hpstrains. These inhibitors are effective against metronidazole-, clarithromycin-, and rifampicin-resistant Hpclinical 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 Hpinfection, they decrease significantly Hpgastric 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 Hpantimicrobial-resistant strains.