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.
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This subpopulation is typically rare, but grows in the presence of the antibiotic (distinguishing this form of subpopulation from persister cells). 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.
The resistant subpopulation is usually in the frequency of 1 resistant cell per 10-1,000,000 total cells in the population. This makes the subpopulation challenging to detect by clinical antimicrobial susceptible testing. These types of tests designate a clinical isolate as resistant or susceptible to an antibiotic, and help guide antibiotic choice for treatment. Thus, if a patient is infected with a heteroresistant isolate, the patient may be treated with the antibiotic to which the isolate has a resistant subpopulation. In that case, the resistant subpopulation may cause the antibiotic therapy to faile. As such, heteroresistance has recently been found to contribute to antibiotics failing during human therapy (Heyman....Andersson et al Lancet Microbe. 2025 Apr;6(4):101010. doi: 10.1016/j.lanmic.2024.101010. and Abbott...Weiss medRxiv. 2025 Mar 13:2025.03.11.25323422.)
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.
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