SalHyd5 · Characterization of Salmonella enterica hydrogenase-5 biosynthesis for developing novel anti-infective compounds

Characterization of Salmonella enterica hydrogenase-5 biosynthesis for developing novel anti-infective compounds

Infections caused by bacteria that have become resistant to antibiotics are rising, making the development of novel anti-infective compounds necessary. In Salmonella enterica serovar Typhimurium the energy conserved by the respiratory oxidation of H2 is crucial for the infection process within the host. The S. enterica genome encodes three [NiFe]-hydrogenases that are involved in H2 oxidation and one of these, termed Hyd-5, is synthesized aerobically and oxides H2 in the presence of O2. S. enterica Hyd-5 cluster encodes three proteins that are only present in aerobic hydrogenase systems. HydH homologs have been proposed as a scaffolding protein for the transfer of the precursor cofactor into the large subunit protecting it against O2. HydF/HydG-like proteins have been reported to be involved in the assembly of the FeS clusters of the small subunit and also in the prevention of the export of the small subunit prior to dimerization with the large subunit. This project was conceived as a clinical need in advance in the knowledge of the mechanisms involved in the biosynthesis and assembly of S. enterica Hyd-5, an O2-tolerant [NiFe]-hydrogenase, as a starting point for the development of novel anti-infectives that could interfere with the virulence of S. enterica and other bacterial pathogens. In addition, understanding the molecular basis of O2-tolerant hydrogenase function has a particular interest in the bioenergy field, in H2 production or in the designing of enzyme-driven fuel cell. In order to circumvent these issues, a first strategy was to consider Hyd-5 as a credible target for the designing of inhibitors that prevent the function of the enzyme. A preliminary bio-layer interferometry (BLI) screen was performed and 28 compounds that interact with the enzyme were identified. One of the objectives of the action was to validate these compounds for their ability to inhibit the Hyd-5 activity. The identification of the interacting points between the enzyme and the most promising potential inhibitor by co-crystallization would gain insight the molecular mechanisms of H2 oxidation and would initiate the development of the anti-infective compounds. The second, and the most promising strategy, was to target the biosynthesis pathway for developing new inhibitors that prevent the assembly of the enzyme. This project emphasizes the importance of considering accessory proteins as target for the development of anti-infective compounds contributing to describe new observations in the field of metalloenzyme assembly.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз