Resistance to standard antibiotic therapies is a growing health concern around the globe. Certain infections that are essentially untreatable have been identified in both hospital and community settings. The increasing frequency of drug resistance has been attributed to a combination of antibiotic over-prescription and societal and technologic changes that affect the transmission of drug-resistant organisms.
The ultimate goal of the research in our laboratory is the structure-based design of novel, therapeutically useful antibiotics and inhibitors of antibiotic-resistance mechanisms. To achieve this goal we use a combination of x-ray crystallography, molecular modelling, molecular docking and molecular biology in collaboration with medicinal chemistry to engineer drugs that specifically interact with and disable critical bacterial target proteins. Specific areas of interest include:
- Bacterial beta-lactamases are enzymes which cleave the four membered beta-lactam ring of the classic family of antibiotics known as the penicillins and cephalosporins. Beta-lactamases are found in dozens of bacterial species, and are a major factor in clinically-observed penicillin resistance. We have determined the high-resolution three-dimensional structure of TEM-1 Beta-lactamase. We have used this structure to design potent inhibitors of the beta-lactamase which protect the penicillin from degradation (thus allowing it to fullfill its antibacterial function). Structural analysis of site-specific mutations of TEM-1 have allowed us to trap various stages in the catalytic pathway, furthering our knowledge of details of the reaction chemistry, which in turn has been used to design more effective inhibitors. Other species of beta-lactamases will also be examined using a similiar approach as to that used for TEM-1.
- Design of novel antibiotics will be pursued through the structural analysis of bacterial enzymes which catalyze crucial reactions in the life-cycle of the bacteria. A large number of enzymes which help to form and rigidify the thick, protective cell-wall of bacteria are a major target area for our efforts. In addition, we will examine a family of membrane-bound bacterial signal peptidases, which perform the critical role of removing the signal peptide from newly synthesized bacterial proteins. Inhibition of any of these enzymes should severely hamper bacterial viability within the human host.