Exploiting commensal-pathogen competition to treat mucosal infection

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Recently, there has been a dramatic rise in the number of bacteria that cause disease acquiring resistance to antibiotics that are commonly used to treat them. These bacteria are known as antimicrobial resistant (AMR) and carry gene/s that mediate insensitivity to, degradation of, or expulsion of, these drugs. In the not too distant future, we are facing a situation where once trivial, easily treatable, infections could potentially prove fatal. Currently, E. coli, a bacterium that constitutes an important part of the normal gut flora, is one of the most frequently isolated AMR hospital acquired infections in Europe and the UK and is a major cause of blood poisoning, diarrhoea and recurrent urinary tract infections. Misuse and overuse of antibiotics (e.g. during chemotherapy or in intensive care units) is at the heart of the AMR problem. However, little research has been performed to date to elucidate the in vivo consequences of AMR in relevant animal models. For the last 20 years my lab has been modelling human intestinal infections with pathogenic E. coli in mice, using the mouse pathogen Citrobacter rodentium. C. rodentium infection is an excellent bacterial colonisation model as it does not cause severe disease in mice. Recently, we found that when treatment of mice infected with C. rodentium that is resistant to the antibiotic kanamycin (Kan), with high level of Kan leads to a phenomenon we termed antibiotic induced bacterial persistence (AIBP). C. rodentium in the AIBP state persists within the gastrointestinal tract for many days and develops a new relationship with the host, which is different from a typical pathogen-host interaction. In particular, virulence genes are turned off in C. rodentium in the AIBP state and the pathogen is non-infectious. In contrast, treating infections with Kan resistant C. rodentium with low levels of Kan leads to delay clearance of the pathogen, which coincided with growth of commensal gut bacteria, which could potentially outcompete or kill C. rodentium.In this study we will characterise C. rodentium in the AIBP state and its relationship with commensal bacteria. Although we appreciate that the mouse intestinal microbiota is not identical to that in humans, this project will reveal common transferable principles underpinning bacterial competition and adaptation in the intestine during antibiotic treatment, the consequences of using the wrong antibiotics to treat AR infections and lead to the identification of novel new natural products expressed by the microbiome that impact on pathogen-host interactions. These principles are likely to be applicable to other enteric pathogens that have to compete with the gut microbiota during colonisation.