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
posted on 2019-06-07, 00:00authored bySandra 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.