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

Abstract

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 broadspectrum antimicrobials. We have designed, synthesized and tested redox variants of nitroethylene-and 7-nitrobenzoxadiazole-based inhibitors of the essential Hp protein 2 Page 3 of 53 3 flavodoxin. Derivatives of the 7-nitrobenzoxadiazole lead, carrying reduced forms of the nitro group and/or oxidized forms of a sulphur 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.

Orally administrated chitosan microspheres bind Helicobacter pylori and decrease gastric infection in mice

“…Regarding CFU counting ( Figure 6.A), average values of infection in H. pylori-infected animals (Hp+) were of 7  10 5 CFU/mice stomach, which corresponds to 10 7 CFU/g of stomach tissue. These values were found similar to the levels reported in literature, which for this SS1 strain has been around 10 5 to 10 8 CFU/g of stomach tissue of H. pylori approximately one month after infection [62,[72][73][74][75][76][77]. In…”

Repurposing Dihydropyridines for Treatment of Helicobacter pylori Infection

“…The increasing resistance to first-line antibiotic drugs, especially metronidazole and clarithromycin [55,56], has had a dramatic impact on the eradication rates, which have fallen to 70% in the last few years [1]. In order to overcome the antimicrobial resistance strategies evolved by this pathogen, novel molecular targets have emerged as candidates for therapeutic interventions [23,24,[57][58][59][60][61]. In a previous work, we validated a new effective anti-H. pylori therapeutic target, the essential response regulator HsrA [17].…”

“…MIC determinations were carried out by the broth microdilution method as previously described [17,23,24]. Briefly, H. pylori strains were grown for 48 h at 37 • C under microaerobic conditions (85% N 2 , 10% CO 2 , 5% O 2 ) in brain heart infusion broth supplemented with 4% fetal bovine serum (BHI+FBS).…”

Flavodoxins as Novel Therapeutic Targets against Helicobacter pylori and Other Gastric Pathogens

“…A second round of optimization was then carried out. To improve the therapeutic and pharmacokinetic properties of compounds I, II, and IV, new variants carrying modified redox forms of nitro, sulfur and vinyl groups of the lead-molecules were synthesized [193]. Derivatives that contain partially or fully reduced forms of the nitro and/or ethylene groups, or partially or fully oxidized forms of the sulfur atom displayed a considerably lower toxicity against HeLa cells and mice than the corresponding leads.…”

“…This selectivity will be useful to minimize the generation of resistances and suggests these inhibitors will be less damaging to the gut microbiota than broad-spectrum antibiotics. Thus, this new family of selective Hp-inhibitors could provide an opportunity for the formulation of therapeutic alternatives to fight Hp-drug resistant strains [193]. As explained, due to the fact of their high selectivity, these Hp-inhibitors will not likely be effective against other pathogens.…”