Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Beta-lactam antibiotics such as the penicillins and cephalosporin's are the largest class of clinically used antibiotics and have had a major impact on human health. However, so-called superbug bacteria have arisen that display complete resistance to all antibiotics. For beta-lactam antibiotics, the most important resistance mechanism is the expression of beta-lactamase enzymes capable of hydrolyzing the lactam ring. This activity renders the antibiotic useless against its usual target (the cell-wall cross linking enzymes known as transpeptidases). Recently, a novel metallo-beta lactamase called NDM-1 has been discovered in enteric bacteria that displays broad spectrum antibiotic resistance. This enzyme poses a serious threat, as there are currently no antibiotics available that can inhibit it. Therefore, the goal of this proposal is to characterize novel NDM-1 inhibitory compounds. Inhibitors discovered using a high throughput screening as well as a recently characterized class of potentially "universal" beta-lactamase inhibitors will be analyzed in complex with the NDM-1 protein. Crystallographic and kinetic analysis will facilitate the characterization of these inhibited enzyme complexes. Taken together, the proposed research will provide structural, mechanistic and kinetic insight into an enzyme that poses a serious threat to human health.