Research Abstracts Online
January 2009 - March 2010
University of Minnesota Twin Cities
Academic Health Center
Center for Drug Design
PI: Courtney Aldrich, Associate Fellow
Design of Antibacterial Agents
A primary objective of this group’s research is to design new antibacterial agents based on novel mechanisms of action. They utilize available data from experimental genetic approaches (random transposon mutagenesis, targeted genetic disruptions) as well as comparison to the human proteome to identify candidate targets. In cases where the structure and enzymology of the enzyme is known, they rationally design substrate mimics or transition-state inhibitors. However, for many potential targets there is inadequate structural information available to permit such a structure-based drug design approach. In these cases, the researchers develop high-throughput-screening assays that allow them to identify a lead candidate molecule. Once a small molecule inhibitor is identified against the targeted enzyme they then apply medicinal chemistry efforts to methodically optimize the inhibitor scaffold. Structure- and/or ligand-based computational approaches are employed to rationalize activity data in order to refine inhibitor design. At an early stage they also test for antibacterial activity against the targeted organism(s) since whole-cell activity is a composite of binding affinity, membrane permeability, and stability. Additionally drug properties of the inhibitors are evaluated using a variety of in vitro assays to examine toxicity, absorption, and metabolism.
The group is using resources at the BMSDL and CGL for this project.
Kimberly Grimes, Research Associate
Amol Gupte, Research Associate
Jessica Keller, Staff
Jõao Neres, Research Associate
Chunhua Qiao, Research Associate
Daniel Wilson, Research Associate