Objectif Recently, the discovery of new antibiotics has slowed, while the incidences of infections caused by bacteria that have become resistant to commonly used antibiotics are rising. There is therefore a growing clinical need for innovative approaches to developing novel anti-infective compounds. Hydrogen is an important energy substrate for a number of pathogenic bacteria and H2 oxidation is essential for the virulence of Salmonella enterica serovar Typhimurium. S. enterica expresses three different H2-uptake [NiFe]-hydrogenases and one of these (termed hydrogenase-5) belongs to a novel class of O2-tolerant hydrogenases that is synthesized aerobically and oxidizes H2 in the presence of O2. The Hyd-5 gene cluster encodes two accessory proteins, HydH and HydG, that are absent in anaerobic systems and are conserved in those systems in which hydrogenases are synthesized in the presence of oxygen. In other systems, HydH homologs have been proposed as scaffolding proteins that bind the immature [NiFe] cofactor prior its transfer to the large subunit of the enzyme. HydG-like proteins are hypothesised to assemble or stabilize the Fe-S clusters of small subunit during biosyntheis. This proposal aims to study the functional role of accessory proteins HydH and HydG in the biosynthesis of Hyd-5 and to design novel small molecule compounds that potentially inhibit hydrogenase activity and assembly. Understanding the mechanisms involved in the biosynthesis of Hyd-5 will allow the development of hydrogenase inhibitors and, as consequence, anti-infectives of virulence of Salmonella and other bacterial pathogens. This project addresses a key biomedical challenge and establishes [NiFe] hydrogenases as novel and credible drug targets. Champ scientifique natural sciencesbiological sciencesmicrobiologybacteriologynatural scienceschemical scienceselectrochemistryelectrolysismedical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibioticsengineering and technologyenvironmental engineeringenergy and fuelsfuel cellsnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Mots‑clés [NiFe]-hydrogenase oxygen tolerance Salmonella hydrogen protein-protein interaction [NiFe] cofactor Fe-S cluster inhibitor Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Thème(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Appel à propositions H2020-MSCA-IF-2014 Voir d’autres projets de cet appel Régime de financement MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinateur UNIVERSITY OF DUNDEE Contribution nette de l'UE € 183 454,80 Adresse Nethergate DD1 4HN Dundee Royaume-Uni Voir sur la carte Région Scotland Eastern Scotland Angus and Dundee City Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 183 454,80