NSF Young Investigator: Studies on Oxidosqualene Cyclase and Catalytic Antibiotics

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9457703 Griffin Stanford University Two major projects will be pursued under this NSF Young Investigator Award: (1) The detailed analysis of oxidosqualene cyclase (OSC) enzymes and (2) The elaboration of antibacterial agents which exhibit catalytic activity towards their cellular targets (i.e., catalytic antibiotics). A long-term goal in the first project will be to gain a detailed mechanistic and structural understanding of OSC enzymes, which catalyze the transformation of oxidosqualene to sterols and related triterpenoids. Inhibitors of OSCs will be prepared that will include inhibitors with promising anti-fungal activity. In the second project, the hypothesis that antibacterial agents which act catalytically against their targets will be more potent than those which act stoichiometrically will be tested. In this study, bacitracin, which sequesters intermediates in cell wall biosynthesis containing bactoprenyl pyrophosphate will be investigated. This grant from the Organic Dynamics Program supports the research of Professor John H. Griffin at Stanford University. The mechanism by which an enzyme affects the cyclization of a molecule into steroids will be pursued and related to the structure of enzyme. From a knowledge of the structure of the enzyme, inhibitors of this enzyme will be prepared that include those with anti-fungal activity. In another project, the mechanism of antibacterial action will be investigated from a molecular perspective. A hypothesis will be tested to determine if antibacterial agents that operate in a catalytic manner are more potent than those that do not.