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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

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posted on 2019-06-07, 00:00 authored by Sandra Salillas, Miriam Alías, Valérie Michel, Alejandro Mahía, Ainhoa Lucía, Liliana Rodrigues, Jessica Bueno, Juan José Galano-Frutos, Hilde De Reuse, Adrián Velázquez-Campoy, José Alberto Carrodeguas, Carlos Sostres, Javier Castillo, José Antonio Aínsa, María Dolores Díaz-de-Villegas, Ángel Lanas, Eliette Touati, Javier Sancho
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.