title: Improved flavodoxin inhibitors with potential therapeutic effects against Helicobacter pylori infection.
abstract: Helicobacter pylori (Hp) infection affects one-half of the human population and produces a variety of diseases from peptic ulcer to cancer. Current eradication therapies achieve modest success rates (around 70%), resistance to the antibiotics of choice is on the rise, and vaccination has not proved to be successful yet. Using an essential Hp protein, flavodoxin, as target, we identified three low-molecular-weight flavodoxin inhibitors with bactericidal anti-Hp properties. To improve their therapeutic indexes, we have now identified and tested 123 related compounds. We have first tested similar compounds available. Then we have designed, synthesized, and tested novel variants for affinity to flavodoxin, MIC for Hp, cytotoxicity, and bactericidal effect. Some are novel bactericidal inhibitors with therapeutic indexes of 9, 38 and 12, significantly higher than those of their corresponding leads. Developing novel Hp-specific antibiotics will help fighting Hp resistance and may have the advantage of not generally perturbing the bacterial flora.
authors.affiliation: Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, 50009, Zaragoza, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Galano
authors.forename: Miriam
authors.initials: M
authors.lastname: Alías
authors.forename: Reyes
authors.initials: R
authors.lastname: Pérez
authors.forename: Adrian
authors.initials: A
authors.lastname: Velázquez-Campoy
authors.forename: Paul S
authors.initials: PS
authors.lastname: Hoffman
authors.forename: Javier
authors.initials: J
authors.lastname: Sancho
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005418:Flavodoxin / Q000037:antagonists & inhibitors*; D006367:HeLa Cells; D016481:Helicobacter Infections / Q000188:drug therapy*; D016480:Helicobacter pylori / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013343:Styrenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001578:Benzopyrans; D005418:Flavodoxin; D010069:Oxadiazoles; D013343:Styrenes