Grant: Operating Grant

Resistance has developed to virtually all antibiotics used in the clinic today. Particularly worrisome are Gram-positive infections caused by organisms such as Staphylococci that cause often-fatal hospital infections and are increasingly a cause for concern in the community setting. The problem is that in the last 40 years or so only two truly novel chemical compounds have been discovered for the treatment of bacterial infections. Indeed most of the antibiotics currently in use were discovered prior to 1960. Since then, the lion's share of antibacterial drug development has involved minor changes to these chemicals. Bacterial resistance to these modified drugs has never been far behind these minor structural changes. Modern approaches to antibacterial drug discovery have emphasized strategies to discover truly novel chemicals with unique mechanisms. The thinking is that a focus on new targets in the bacteria will give rise to new chemical matter that kill bacteria with novel mechanisms for which there are no pre-existing resistance mechanisms. The problem with this approach is that bacterial physiology and the interactions of bacterial pathogens with patients are remarkably complex. Success in drug discovery is critically dependent on a deep understanding of the biology behind new targets. In the work proposed here we are laying the groundwork for a meticulous understanding of the physiology of wall teichoic acid synthesis in Gram-positive bacteria. Our work aims to test the hypothesis that wall teichoic acid is a critically important component of the cell walls of pathogens like Staphylococcus aureus and that there are druggable targets in the teichoic acid biosynthetic pathway. Ultimately, it is hoped that these studies will contribute to the development of new antibacterial drugs.