β-Lactams, a group that includes penicillins, cephalosporins, and carbapenems, are the most widely prescribed class of antibiotics. However, clinical use of β-lactams is critically threatened by bacterial resistance, particularly via the production of β-lactamase enzymes.
Our group studies β-lactam antibiotics, the β-lactamases that degrade them, and the transpeptidases that they target. We use a multidisciplinary approach, combining chemical, biochemical, biophysical, and microbiological techniques. Areas of research include:
All β-lactam antibiotics, including those in the clinical development pipeline, can be degraded by β-lactamases. We aim to understand the mechanisms by which β-lactamases degrade the different kinds of β-lactams, and how these enzymes might evolve in response to new antibiotics.
In particular, we focus on carbapenemases, β-lactamases that degrade carbapenems. We recently found that a major class of β-lactamases degrade carbapenems through a previously unidentified mechanism involving lactone formation:
We are now investigating the mechanistic aspects of lactone formation, the biological activities of this product, and the relationship between lactone formation and antibiotic resistance.
Rapid detection of β-lactamase-producing bacteria is critical in clinical and environmental contexts. Working with collaborators, we are developing new strategies for detecting β-lactamase activity. In addition, we are applying these approaches to identify and characterize β-lactamase inhibitors.
Transpeptidases and Peptidoglycan
β-Lactams target bacterial transpeptidase enzymes, inhibiting the synthesis of cell wall peptidoglycan. We are studying the mechanisms by which β-lactams interact with transpeptidases.
The L,D-transpeptidases (Ldts), promising antibiotic targets in Mycobacterium tuberculosis, are potently inhibited by some β-lactam antibiotics. We recently found that Ldts are able to degrade β-lactams through several mechanisms. We are now examining the scope of this activity, and its relevance in a biological context. Based on these mechanistic studies, we aim to develop new strategies for inhibiting Ldt activity.
The biosynthetic pathways for β-lactam natural products have evolved alongside the enzymes that confer resistance to them. Based on our mechanistic studies with β-lactamase enzymes, many of these natural products are likely to be resistant to β-lactamase catalysis. We study how these β-lactams are biosynthetically assembled, and characterize their interactions with β-lactamases and transpeptidases.