Antibiotic resistance in Gram-negative pathogens is a growing challenge and a leading cause of death globally. As new antibiotics are introduced, clinical isolates develop resistance through genetic or phenotypic changes, making the antibiotic less effective. Conventionally, if a bacterial isolate develops antibiotic resistance,  every cell in the population exhibits resistance and survives antibiotic exposure. However, many Gram-negative isolates exhibit a unique form of resistance called heteroresistance: rather than the entire population, only a minority subpopulation exhibits resistance to the antibiotic. This subpopulation is typically rare, grows in the presence of the antibiotic, and is challenging to detect by clinical testing. These features allow the subpopulation to be dynamic; the resistant cells are enriched during antibiotic exposure but return to baseline minority frequency when the antibiotic exposure ends. Heteroresistance is common to many antibiotic classes and has recently been found to contribute to antibiotics failing during human therapy.

Heteroresistance is a form of phenotypic heterogeneity in a population, therefore we are interested in deciphering mechanisms that allow cells of the same population to exhibit different features. We seek to understand the mechanisms that generate antibiotic heteroresistance to different antibiotics, particularly cephalosporins, in Enterobacter and similar Gram-negative species isolated from human infections. We are also interested in pathways that support resistance, and mechanisms that generate heterogeneity in other types of phenotypes. Our long-term goal is to improve antibiotic development and treatment by providing insights into antibiotic resistance, heteroresistance, and fundamental bacterial biology.