Aldrich Research Home

Courtney C. Aldrich
Associate Professor, Center for Drug Design
Associate Director, Center for Drug Design

Contact information:
Office: 7-224 Phillips Wangensteen
Phone: 612-625-7956
Fax: 612-625-8154
E-mail: aldri015@umn.edu

Education:
B.S., University of Missouri, St. Louis, 1994
Ph.D., UCLA, 2001

Research Interest:
A primary objective of our research is to design new antibacterial agents based on novel mechanisms of action. Currently, all clinically used antibiotics act by one of a limited number of mechanisms (e.g. inhibition of protein synthesis, DNA synthesis, cell-wall synthesis, and RNA transcription). We utilize available data from experimental genetic approaches (random transposon mutagenesis, targeted genetic disruptions) as well as comparison to the human proteome to identify candidate bacterial targets. In cases where the structure and enzymology of the bacterial enzyme is known, we 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 we develop high-throughput-screening (HTS) assays that allow us to identify a lead candidate molecule. Once a small molecule inhibitor is identified against the targeted enzyme we 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 we 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 our inhibitors are evaluated using a variety of in vitro assays to examine toxicity, absorption, and metabolism. Using this approach we developed a new class of antibiotics that act by disruption of bacterial iron acquisition. We identified a previously unexplored target (an enzyme known as MbtA involved in biosynthesis of the mycobactins, which are small-molecule iron-chelators produced by Mycobacterium tuberculosis) and described the design, synthesis, and biochemical evaluation of picomolar inhibitors effective against MbtA that also possess potent in vivo activity against Mycobacterium tuberculosis. Since tuberculosis is the leading cause of bacterial infectious disease mortality this research is expected to have a positive impact on human health and may additionally validate a new class of antibiotics that target siderophore biosynthesis.