Research Interests

 
 

Resistance to antibiotics by pathogenic microorganisms poses significant problems to human health.  Research and development on novel antibiotics has lagged behind the rise in drug resistance seen in microbial populations.  This research project one part of a three-part, interdisciplinary effort by Peggy Richey, Jennifer Muzyka and January Haile to identify novel antibacterial drugs. The goals of the research are to identify antibacterial drug candidates via computer-aided structure-based ligand screening and design (Muzyka), assay candidate inhibitors for antibacterial activity (Richey), and characterize the biochemical properties (enzyme kinetics) of inhibitors that display antibacterial activity (Haile).  This kind of approach has been successful in the development of several drugs that are commercially available, including HIV protease inhibitors. 


An antibacterial drug is likely to be most successful if it is directed at enzymes which are necessary to the survival of bacteria but have no human analog.  Thus, the Mur family of enzymes (MurA-MurF) has been selected for study as they catalyze the biosynthesis of peptidoglycan in the bacterial cell wall.  Without peptidoglycan, the cell wall has less mechanical strength and is unable to resist forces of osmotic pressure. Human cells do not have cell walls and are not affected by drugs that target the cell wall. The mechanisms of action for these enzymes have been studied and their X-ray crystal structures are known.  Derivatives of phosphinic acid inhibit Mur C through Mur F; however, only one FDA-approved antibiotic (fosfomycin) targets an enzyme in this family, MurA.  Recent research has uncovered ligands (molecules that bind to another molecule) which bind to and inhibit these enzymes, but most of these compounds do not exhibit antibacterial activity.

If you’re interested in a research experience either during the semester or summer, contact me

 

PDB view of MurA crystal structure