Our group is interested in the mechanisms by which antibiotics target bacterial cells, and the mechanisms by which bacteria become resistant to antibiotics. We use a multidisciplinary approach in our lab, combining chemical, biochemical, biophysical, and microbiological techniques.
Most of our work is focused on the β-lactams (e.g., penicillins, cephalosporins, and carbapenems), the most widely prescribed class of antibiotics.
Bacteria can become resistant to β-lactams through several different mechanisms. One of the most important resistance mechanisms among Gram-negative bacteria involves the production of β-lactamases, enzymes that degrade β-lactams and prevent them from targeting bacterial cells.
Some of our current work is focused on:
Factors that impact β-lactamase activity and mechanism
β-lactamases have evolved in the context of the bacterial periplasm, and the activity of these enzymes may be impacted by other components in this environment. We are currently investigating the interactions between β-lactamases and other bacterial proteins, exploring how efficiently β-lactamases degrade β-lactam antibiotics.
Bacteria can cause infections in different parts of the human body, and these different environments have different physicochemical properties. We are examining how these properties impact β-lactamase activity, and in turn are determining how this impacts the susceptibility of bacterial cells to β-lactam antibiotics.
Roles of resistant bacteria to microbial communities
Resistant bacteria that produce β-lactamases degrade β-lactam antibiotics in their environment, protecting other bacteria that would otherwise be susceptible to these antibiotics. We are exploring the relevance of this antibiotic “sheltering” in microbial communities, especially those that contribute to polymicrobial infections (e.g., cystic fibrosis).
We have developed a luminescence assay that we are using to quantify antibiotic sheltering. We are currently investigating genetic factors and environmental conditions that influence sheltering, with the goal of understanding how these factors impact the efficacy of antimicrobial chemotherapy
Detection of β-lactamase-producing bacteria
The ability to rapidly identify β-lactamase-producing bacteria is critical in order to determine the optimal treatment for a bacterial infection, and to prevent the spread of resistant microbes.
We and our collaborators are exploring new strategies for detecting bacteria that produce β-lactamases. Our goal is to develop approaches that can be applied to the identification of resistant microbes directly from clinical samples.
Discovery of new antibiotics and β-lactamase inhibitors
Bacteria have resistance mechanisms that can protect against all clinically used antibiotics, including all of the different kinds of β-lactam antibiotics. While inhibitors have been developed to block β-lactamase-catalyzed β-lactam degradation (e.g., clavulanic acid, avibactam), this selects for bacteria that produce new β-lactamases which are less susceptible to these inhibitors.
Our group has developed a whole-cell biosensor that can be applied to the discovery of antibacterials and β-lactamase inhibitors. Working with collaborators at Queen’s University, we are using this biosensor to screen natural products for activity against resistant bacteria.