Antibiotics are a double-edged sword: they are crucial for treating bacterial infections, but they can also cause significant collateral damage to the microbiota. Antibiotics supress the growth of commensal microorganisms and at the same time select for drug-resistance. Individuals are often benignly colonized with resistant potential pathogens persisting at low levels within their microbiota. Antibiotics can lead to overgrowth and spread of these resistant pathogens to other body sites, such as the bloodstream, leading to hard-to-treat resistant superinfections. This is a particular concern for patients colonized with pathogens resistant to last resort antibiotics, such as carbapenem resistant Enterobacteriaceae. The behaviour of resistant strains within the microbiota during treatment depends on the specific antibiotic and resistance mechanism, as well as the makeup of the other bacteria present in the microbiota.
This project will take an interdisciplinary approach to determine the fundamental rules that describe and predict how antibiotic treatment will perturb an individual’s microbiota, particularly when colonised with resistant potential pathogens. Building on our previous work (Stracy et al. Science. 2022, 375 (6583), 889-894)), we will focus on extra-intestinal pathogenic Escherichia coli (ExPEC), which is commonly resistant and can persist in the gut microbiota asymptomatically over long periods. In particular, we aim to systematically determine and deconvolve mechanisms by which antibiotics cause dysbiosis to commensal species and overgrowth of resistant ExPEC within the gut microbiota.
To achieve this, we will use experimental approaches with microbial communities in vitro and in vivo, together with microscopy methods to unravel the effect of antibiotics on the micro-scale biogeography of the gut microbiota. By combining this data with mathematical analysis, we will build a predictive model to identify patients with microbiomes at high risk of antibiotic-induced resistant-strain overgrowth and test approaches to modify the microbiota to minimise antibiotic-induced pathogen overgrowth.