Isoprenoid Biosynthesis: A target for drugs against category A-C pathogens
Institution: Colorado State University (CSU), Department of Microbiology, Immunology and Pathology, Fort Collins, Colorado
Principal Investigator: Dean Crick, Ph.D.
Co-Investigator: Pat Brennan, Ph.D. - CSU
Collaborators and Core Labs:
a) Genomics/Proteomics Core – CSU Echelon Biosciences, Inc – Salt Lake City, UT
b) Small Molecule Screening Laboratory – Harvard University, Boston, MAExpected Product: Identification of novel broad-spectrum therapeutic candidates effective against gram negative bacterial pathogens.
Introduction:
The NIAID biodefense research agendas for category A-C agents have identified a need for a broader, more robust arsenal of anti-infective agents. This is important when considered in the light of recent research in genomics and immunology, which has greatly eased the task of genetic manipulation of pathogens. Modified bacteria could be created that are both resistant to treatment with current antimicrobials and difficult to identify. Our project is designed to address knowledge gaps in key aspects of the physiology of Category A-C pathogens that are fundamental to product development. The cell envelope presents the interface between bacterial pathogen and host cell and is the focal point, in the case of many pathogens, for the development of new narrow-spectrum drugs and vaccines. Key components of the synthesis of bacterial cell-walls are those lipids involved in the biosynthesis of many essential structural elements. These lipids often play integral roles in maintaining the integrity of the cell-wall as well. Thus, the specific aim of this grant is identification and validation of potential drug targets involved in isopenetnyl diphosphate biosynthesis in select agents of bioterrorism. Enzymes to be studied include those involved in the mevalonate independent synthesis of isopentenyl diphosphate. Study of these potential drug targets will involve cloning, expression and kinetic characterization, followed by development of high throughput screening (HTS) assays to identify compounds for drug development.