Grant: Operating Grant

Antibiotic resistance is a serious and rapidly escalating health care problem. We are faced with the prospect of growing numbers of pan-resistant bacteria - bacteria resistant to every known antibiotic. We study two types of enzymes that bacteria need to survive. The carboxyvinyl transferases synthesize the aromatic amino acids and components of the cell wall. The carboxyketose synthases are a group of three enzymes which produce unusual sugars that bacteria require. One sugar is a building block for aromatic compounds, another forms part of the bacterial cell's outer surface, and the third helps bacteria evade the immune system. We use a variety of techniques to gain a detailed understanding of the reactions catalyzed by our target enzymes, including determining the structures of the high-energy species by measuring kinetic isotope effects, determining reaction rates, determining the enzymes' structures, and designing and testing new enzyme inhibitors. Having a thorough understanding of how the enzymes work allows us to design new inhibitors. These inhibitors will have the potential to become new antibiotics to treat bacterial infections.