Selective Targeting of Human and Animal Pathogens of the Helicobacter Genus by Flavodoxin Inhibitors: Efficacy, Synergy, Resistance and Mechanistic Studies

Author:

Salillas Sandra,Galano-Frutos Juan JoséORCID,Mahía AlejandroORCID,Maity RitwikORCID,Conde-Giménez María,Anoz-Carbonell Ernesto,Berlamont HelenaORCID,Velazquez-Campoy AdrianORCID,Touati Eliette,Mamat Uwe,Schaible Ulrich E.ORCID,Gálvez José A.ORCID,Díaz-de-Villegas María D.,Haesebrouck FreddyORCID,Aínsa José A.ORCID,Sancho JavierORCID

Abstract

Antimicrobial resistant (AMR) bacteria constitute a global health concern. Helicobacter pylori is a Gram-negative bacterium that infects about half of the human population and is a major cause of peptic ulcer disease and gastric cancer. Increasing resistance to triple and quadruple H. pylori eradication therapies poses great challenges and urges the development of novel, ideally narrow spectrum, antimicrobials targeting H. pylori. Here, we describe the antimicrobial spectrum of a family of nitrobenzoxadiazol-based antimicrobials initially discovered as inhibitors of flavodoxin: an essential H. pylori protein. Two groups of inhibitors are described. One group is formed by narrow-spectrum compounds, highly specific for H. pylori, but ineffective against enterohepatic Helicobacter species and other Gram-negative or Gram-positive bacteria. The second group includes extended-spectrum antimicrobials additionally targeting Gram-positive bacteria, the Gram-negative Campylobacter jejuni, and most Helicobacter species, but not affecting other Gram-negative pathogens. To identify the binding site of the inhibitors in the flavodoxin structure, several H. pylori-flavodoxin variants have been engineered and tested using isothermal titration calorimetry. An initial study of the inhibitors capacity to generate resistances and of their synergism with antimicrobials commonly used in H. pylori eradication therapies is described. The narrow-spectrum inhibitors, which are expected to affect the microbiota less dramatically than current antimicrobial drugs, offer an opportunity to develop new and specific H. pylori eradication combinations to deal with AMR in H. pylori. On the other hand, the extended-spectrum inhibitors constitute a new family of promising antimicrobials, with a potential use against AMR Gram-positive bacterial pathogens.

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference71 articles.

1. Pathogenesis and clinical management of Helicobacter pylori gastric infection

2. Chapter 7–Helicobacter pylori;Percival,2014

3. From inflammation to gastric cancer: Role of Helicobacter pylori

4. Pathogenesis of Helicobacter pylori infection

5. Agents Classified by the IARC Monographs, Volumes 1–129 https://monographs.iarc.who.int/list-of-classifications

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