Research in my laboratory concerns investigating the structure and function relationship of enzymes involved in the metabolism of the essential bacterial cell wall polymer peptidoglycan. Peptidoglycan is a heteropolymer of both amino-sugars and short peptides that completely surrounds bacterial cells as a single macromolecule to provide their rigidity and structure. Its biosynthesis occurs in three stages involving the cytoplasm, the cytoplasmic membrane, and the cell wall. Specific reactions in each of these stages have proven to be effective targets for antibiotic therapy, including the inhibition of peptide cross-linking within the cell wall by the ß-lactam class of drugs (penicillins and celphalosporins). Our studies focus on the events within the cell wall with the aim to identify new potential targets for antibiotic development.
The search for new antibiotic targets provide fascinating challenges for experimental research involving a wide range of experimental approaches that span the biochemistry, biophysics, microbiology, molecular biology, and structural biology.
Current areas of emphasis include:
- Structure and function of the lytic transglycosylases, endogenous 'autolysins' that are involved in the biosynthesis and turnover of peptidoglycan, and the insertion of multi-protein complexes through the cell wall, such as flagella, pili, and secretion systems.
- The role of proteinaceous inhibitors of lysozyme in the physiological control of lytic transglycosylases.
- Characterization of the enzyme systems required for the O-acetylation of peptidoglycan in both Gram positive and Gram negative bacteria, using primarily Bacillus anthracis, Staphylococcus aureus and Neisseria gonorrhoeae as model systems.
- High-throughput screening for inhibitors of peptidoglycan O-acetyltransferases and O-acetylesterases
- Determination of X-ray crystal structures of O-acetyltransferases.
- Structural basis for substrate recognition and inhibition of O-acetylpeptidoglycan esterases.