D-alanine:D-alanine Ligase as an Antibacterial Target for S. Aureus (#38)
Andrew Thompson
1
,
Steven Polyak
1
,
Andrew Abell
1
,
John Bruning
1
- The University of Adelaide, Adelaide, SA, Australia
| Staphylococcus aureus infections and bacteremia rates are on the rise bringing with them a significant cost to the health care system while posing a very high mortality rate. These infections are also becoming increasingly difficult to treat due to multi-drug resistance to current antibiotics. There is a desperate need for new antibiotics to combat resistant S. aureus strains and hence new drug targets are needed. One such attractive target is the essential enzyme D-Alanine- D-Alanine ligase (Ddl) which synthesizes a D-ala:D-ala peptide critical for peptidoglycan formation and cell wall integrity. Humans lack this enzyme and the necessity for D-ala:D-ala peptides further highlighting the attractiveness of this target. We have 1) identified two potent lead compounds, 2) solved the structure of the enzyme in complex with the inhibitors, 3) have demonstrated an MIC value in the low microgram/mL range including resistant clinical strains, and 4) we have produced preliminary pharmacokinetic data for each compound. As such, this talk will discuss how are team have implemented biochemistry, X-ray crystallography, microbiology and animal models of Staphylococcus infection to develop these novel antimicrobials. |