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

Design, synthèse et test d'efficacité des inhibiteurs de flavodoxine, Nitroethylene- et 7-Nitrobenzoxadiazole contre les souches clinniques antibio-resistantes d'Helicobacter pylori et dans les souris infectées

Sandra Salillas (1, 2, 3) , Miriam Alías (1, 3) , Valérie Michel (4) , Alejandro Mahía (1, 2, 3) , Ainhoa Lucía (2, 5, 6) , Liliana Rodrigues (2, 6, 5) , Jessica Bueno (6) , Juan José Galano-Frutos (1, 3, 2) , Hilde de Reuse (4) , Adrián Velázquez-Campoy (1, 3, 2, 7) , José Alberto Carrodeguas (1, 3, 2) , Carlos Sostres (8, 2) , Javier Castillo (6) , José Antonio Aínsa (6, 1, 2, 5) , María Dolores Díaz-De-Villegas (9) , Angel Lanas (10, 2, 5) , Eliette Touati (4) , Javier Sancho (1, 2, 3)

1 BIFI - Instituto de Biocomputación y Física de Sistemas Complejos = Institute for Biocomputation and Physics of Complex Systems
2 Aragón Health Research Institute [Zaragoza, Spain]
3 Departamento de Bioquímica y Biología Molecular y Celular [Zaragoza]
4 Pathogenèse de Helicobacter - Helicobacter Pathogenesis
5 CIBERES - Centro de Investigación Biomédica en Red Enfermedades Respiratorias
6 Departamento de Microbiología, Medicina Preventiva y Salud Publica [Zaragoza]
7 ARAID - Fundación Agencia Aragonesa para la Investigación y el Desarrollo
8 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
9 Instituto de Síntesis Química y Catálisis Homogénea
10 Departamento de Medicina, Psiquiatría y Dermatologíae [Zaragoza, Spain]

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.

Domaines: Maladies infectieuses; Chimie thérapeutique

Sandra Salillas, Miriam Alías, Valérie Michel, Alejandro Mahía, Ainhoa Lucía, et al.. 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. Journal of Medicinal Chemistry, 2019, 62 (13), pp.6102-6115. ⟨10.1021/acs.jmedchem.9b00355⟩. ⟨pasteur-02868148⟩