Sulfur Assimilation Inhibitors

Design, Synthesis and Optimisation of Inhibitors of Enzymes Involved in the Sulfur Assimilation Pathway in Gram-negative Bacteria (WP1, WP2)

Prof. Gabriele Costantino
University of Parma

Availability of cysteine is crucial for bacteria since this amino acid is the preferential source of sulfur for all sulfur-containing biological molecules, such as methionine, biotin, thiamin and iron–sulfur clusters. The final two steps of cysteine biosynthesis in the sulfur assimilation pathway are carried out by serine acetyl transferase (SAT) and O-acetylserine sulfhydrylase (OASS). By following preliminary results, we will focus on design and synthesis of novel series of chemo-types, active towards the two OASS isoforms of Gram-negative bacteria, specifically S. typhimurium, exploiting the active site geometry and the coenzyme reactivity. We will also investigate the catalytic and regulatory properties of SAT as a prerequisite for the identification of selective inhibitors. The inhibitors will be used to assess the druggability of these enzymes as Gram-negative antibacterial agent target. Our final goal, given that cysteine acts as feedback inhibitor of SAT is the design of dual-specific ligands for SAT and OASS. In order to discover novel inhibitors for the enzymes of bacterial sulfur metabolism, our project involves structure-based development of competitive inhibitors of OASS-A, OASS-B and SAT.

Objectives:  Rational design and synthesis of a series of conformationally restricted small molecules inhibitors of OASS-A, OASS-B, and SAT, enzymes involved in the last steps of sulfur assimilation pathway. Optimization of their PK properties.

Expected Results: Identification of at least one hit compound for each studied enzyme and optimization of the their properties towards a hit-to-lead progression.

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska Curie grant agreement No  642620
European Union