Mouse Model; Evolution; E. coli; Phylodynamics; Antibiotic resistance; Plasmid
Carroll Laura M., Huisman Jana S., Wiedmann Martin (2020), Twentieth-century emergence of antimicrobial resistant human- and bovine-associated Salmonella enterica serotype Typhimurium lineages in New York State, in Scientific Reports
, 10(1), 14428-14428.
Bakkeren Erik, Diard Médéric, Hardt Wolf-Dietrich (2020), Evolutionary causes and consequences of bacterial antibiotic persistence, in Nature Reviews Microbiology
, 18(9), 479-490.
Wotzka Sandra Y., Kreuzer Markus, Maier Lisa, Arnoldini Markus, Nguyen Bidong D., Brachmann Alexander O., Berthold Dorothée L., Zünd Mirjam, Hausmann Annika, Bakkeren Erik, Hoces Daniel, Gül Ersin, Beutler Markus, Dolowschiak Tamas, Zimmermann Michael, Fuhrer Tobias, Moor Kathrin, Sauer Uwe, Typas Athanasios, Piel Jörn, Diard Médéric, Macpherson Andrew J., Stecher Bärbel, Sunagawa Shinichi, et al. (2019), Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice, in Nature Microbiology
, 4(12), 2164-2174.
Tepekule Burcu, Abel zur Wiesch Pia, Kouyos Roger D., Bonhoeffer Sebastian (2019), Quantifying the impact of treatment history on plasmid-mediated resistance evolution in human gut microbiota, in Proceedings of the National Academy of Sciences
, 116(46), 23106-23116.
Bakkeren Erik, Huisman Jana S., Fattinger Stefan A., Hausmann Annika, Furter Markus, Egli Adrian, Slack Emma, Sellin Mikael E., Bonhoeffer Sebastian, Regoes Roland R., Diard Médéric, Hardt Wolf-Dietrich (2019), Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut, in Nature
, 573(7773), 276-280.
To improve our strategies to combat antibiotic resistance we urgently need a better quantitative understanding of where resistance arises and how it spreads. However, given the multitude of environments in which bacteria are exposed to antibiotics and the multitude of pathways by which resistance can travel between environments, obtaining such a quantitative understanding is a formidable challenge. In this proposal we focus on plasmids and their role in the emergence of antibiotic resistance. The central objective is to create new inroads into the quantification of the contribution of plasmids to resistance evolution at three levels of granularity and to integrate the quantitative results obtained by means of mathematical modelling. First, at the ecological level, we will develop new phylogenetic/dynamic methods that quantify the exchange of antibiotic resistance between compartments by reconstructing the plasmid transmission history. Second, at the level of the infected host, we aim to quantify rates of plasmid transfer within the microbial community inside an individual host focussing on Escherichia coli isolates with key resistance mechanisms (e.g. extended-spectrum beta-lactamases, ESBLs) and using well-defined mouse models to study plasmid transfer as a function of gut microbiota composition, enteric disease and the presence of antibiotics. Third, at the level of individual bacterial populations, we will use high-throughput in vitro experiments to identify parameters that determine rates of plasmid spread across genotypes and environments. Finally, with the view towards improved risk assessment and control strategies, we will develop mathematical models that describe the dynamics of spread of plasmid conferred resistance at all levels. Our interdisciplinary team brings together the relevant backgrounds of microbiology, evolutionary biology, infectious disease ecology and mathematical biology.