Sialic Acid Scavenging, Catabolic and Sialylation Pathways: Putative Targets for New Antimicrobial Agents

Purpose and goal

This project aimed to study bacterial enzymes and transport proteins active in catabolism and uptake of sialic acid, a sugar molecule present in the host. The insights gained about protein structure and function was utilised in computer-aided design of new molecules with the potential to inhibit the proteins. Such molecules were hypothesised to constitute a conceptually completely new class of antibiotics.

Expected results and effects

The key results reached were: X-ray structures and homology models of target proteins in complexes with sialic acid were determined to provide new knowledge about structure and function. The structures enabled design and synthesis of new molecules as inhibitors of the transport proteins. The new inhibitors were evidenced to block sialic acid transport and growth of P. mirabilis. Hence, the overall outcome was new knowledge about the structure and function of bacterial transport proteins, as well as the discovery of a conceptually new class of antibacterial molecules.

Planned approach and implementation

Target proteins were crystallized in complexes with sialic acid. X-ray crystallography provided information on structure and function and laid the foundation for computer-aided design of new potential inhibitors. Synthesis of designed molecules led to discovery of potent inhibitors. An inhibitor blocked sialic acid uptake via SiaT transporters of P. mirabilis and S. aureus in proteosome assay. An inhibitor was a potent inhibitor of P. mirabilis growth on sialic acid medium. Together, new structural biology gave rise to the discovery of a new class of antibacterial molecules