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Towards quantification of the contribution of plasmids to the spread of antibiotic resistance

English title Towards quantification of the contribution of plasmids to the spread of antibiotic resistance
Applicant Bonhoeffer Sebastian
Number 167121
Funding scheme NRP 72 Antimicrobial Resistance
Research institution Gruppe Theoretische Biologie Departement Umweltsystemwissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Microbiology
Start/End 01.03.2017 - 30.06.2020
Approved amount 648'021.00
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All Disciplines (2)

Discipline
Experimental Microbiology
Ecology

Keywords (6)

Mouse Model; Evolution; E. coli; Phylodynamics; Antibiotic resistance; Plasmid

Lay Summary (German)

Lead
Bakterien geben untereinander sogenannte Plasmide weiter, die genetische Informationen zur Resistenzbildung enthalten. Wir erforschen deren Rolle und analysieren Faktoren, die den Austausch von Plasmiden beschleunigen.
Lay summary

Antibiotikaresistenzen verbreiten sich unter anderem, indem Bakterien untereinander genetisches Material transferieren. Dazu zählen Plasmide. Um deren Rolle zu klären, schätzen wir zunächst mit bioinformatischen Methoden ab, wie oft verschiedene Bakterienarten Plasmide austauschen. Diese Transferhäufigkeit messen wir auch im Tiermodell, bei Darmbakterien der Maus, unter dem Einfluss verschiedener Faktoren wie Entzündungen oder geringen Antibiotikakonzentrationen. Anschliessend erheben wir die Transferhäufigkeit von Plasmiden in Bakterienkulturen im Labor. Aufgrund aller erhobenen Daten entwickeln wir mathematische Modelle, die berechnen, welche Faktoren sich wie auf die Transferrate von Plasmiden und somit auf die Weitergabe von Resistenzen auswirken.

Hintergrund
Obwohl Plasmide eine wichtige Rolle bei der Entstehung und Verbreitung von Antibiotikaresistenzen spielen, fehlen bisher genaue Kenntnisse zur Häufigkeit der Übertragung von Plasmiden und wie diese beeinflusst wird.

Ziel
Unser Ziel ist die Entwicklung mathematischer Modelle, um zu berechnen, wie schnell sich Resistenzen durch Plasmidtransfer verbreiten können.

Bedeutung
Unsere Modelle sollen bestimmte Situationen erkennen, beispielsweise im Krankheitsverlauf von Patienten, welche den Austausch von Resistenzinformationen zwischen Erregern begünstigen. Dieses Wissen kann helfen, rechtzeitig entsprechende Gegenmassnahmen zu ergreifen.

Direct link to Lay Summary Last update: 08.12.2017

Lay Summary (French)

Lead
Les bactéries échangent entre elles des molécules appelées plasmides qui contiennent des informations génétiques relatives au développement de résistances. Nous étudions leur rôle et nous analysons les facteurs qui accélèrent leur transfert.
Lay summary

Les résistances aux antibiotiques se propagent entre autres parce que les bactéries échangent entre elles du matériel génétique, dont les plasmides font partie. Afin de clarifier leur rôle, nous évaluerons grâce à des méthodes bioinformatiques à quel rythme différentes bactéries échangent des plasmides. Cette fréquence sera aussi mesurée sur un modèle animal, les bactéries intestinales de la souris, soumises à l’influence de plusieurs facteurs, notamment des faibles concentrations d’antibiotiques. Nous étudierons également la fréquence de ces transferts dans des cultures in-vitro. Les données recueillies serviront à élaborer des modèles mathématiques afin de calculer quels sont les facteurs qui influent sur les transferts de plasmides et, conséquemment, sur la propagation des résistances.

Contexte
Bien que les plasmides jouent un rôle important dans l’apparition et la propagation des résistances, nous manquons encore de connaissances exactes sur leur fréquence de transmission et les facteurs qui influencent celle-ci.

Objectif
Notre objectif est de développer des modèles mathématiques permettant de calculer à quelle vitesse des résistances peuvent se propager par l’intermédiaire du transfert de plasmides.

Importance
Nos modèles doivent permettre d’identifier des situations précises – par exemple en fonction de l’évolution de la maladie chez les patients – qui favorisent l’échange d’informations de résistance entre agents pathogènes. Ces connaissances peuvent ainsi aider à prendre les mesures qui s’imposent en temps utile.


Direct link to Lay Summary Last update: 08.12.2017

Lay Summary (English)

Lead
Bacteria exchange plasmids that contain genetic information involved in the development of resistance. We are researching their role and analysing factors that accelerate plasmid exchange.
Lay summary

One of the ways in which antibiotic resistance spreads is by bacteria transferring genetic material among themselves. This material includes plasmids. In order to clarify the role played by plasmids, we first use bioinformatic methods to estimate how often different types of bacteria exchange plasmids. We also measure this transfer frequency in an animal model using mouse gut bacteria under the influence of different factors such as inflammation or low concentrations of antibiotic. We then record the transfer frequency of plasmids in bacterial cultures in the laboratory. We use all the recorded data to develop mathematical models that calculate the effect of different factors on the transfer rate of plasmids and thus on the transfer of resistance.

Background
Although plasmids play an important role in the development and spread of antibiotic resistance, there is currently no precise information on the frequency with which plasmids are transferred and the factors that influence this process.

Aim
Our goal is to develop mathematical models to calculate the speed at which resistance can be spread by plasmid transfer.

Relevance
Our models will allow doctors and medical researchers to recognise certain situations, for example in the course of a patient’s illness, that are conducive to the exchange of resistance information between pathogens. This knowledge can help ensure that effective countermeasures are taken in good time.


Direct link to Lay Summary Last update: 08.12.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Twentieth-century emergence of antimicrobial resistant human- and bovine-associated Salmonella enterica serotype Typhimurium lineages in New York State
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.
Evolutionary causes and consequences of bacterial antibiotic persistence
Bakkeren Erik, Diard Médéric, Hardt Wolf-Dietrich (2020), Evolutionary causes and consequences of bacterial antibiotic persistence, in Nature Reviews Microbiology, 18(9), 479-490.
Escherichia coli limits Salmonella Typhimurium infections after diet shifts and fat-mediated microbiota perturbation in mice
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.
Quantifying the impact of treatment history on plasmid-mediated resistance evolution in human gut microbiota
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.
Salmonella persisters promote the spread of antibiotic resistance plasmids in the gut
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.

Collaboration

Group / person Country
Types of collaboration
Sarah Tschudin / Unispital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Arjan de Visser, Wageningen University Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Sarah Duxbury, de Visser Lab, Wageningen University Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Egil Fischer, Universiteit Utrecht Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
EMBO/EMBL Symposia: New Approaches and Concepts in Microbiology Talk given at a conference Antibiotic tolerant Salmonella cells can promote the spread of resistance plasmids 10.07.2019 Heidelberg, Germany Bakkeren Erik;
Modelling in Ecology and Evolution Zurich Talk given at a conference Quantifying migration rates in the presence of deme dependent sampling 27.06.2019 Zurich, Switzerland Huisman Jana Sanne;
Plasmid-AMR Meeting Talk given at a conference The phylodynamics of MDR plasmids and their hosts 05.06.2019 Utrecht, Netherlands Huisman Jana Sanne;
Plasmid-AMR Meeting Poster Antibiotic resistance plasmids spread at diverse rates through recipient populations, in the absence of selection 05.06.2019 Utrecht, Netherlands Benz Fabienne;
Plasmid-AMR Meeting Talk given at a conference Phenotypic delay and the estimation of conjugation rates 05.06.2019 Utrecht, Netherlands Bonhoeffer Sebastian;
Plasmid-AMR Meeting Talk given at a conference Resistance evolution of E. coli in populations and communities 05.06.2019 Utrecht, Netherlands Hall Alex;
National Research Programme 72 Meeting Poster Antibiotic tolerant Salmonella cells can promote the spread of resistance plasmids 27.03.2019 Lausanne, Switzerland Bakkeren Erik;
National Research Programme 72 Meeting Poster Extended-spectrum beta-lactamase (ESBL) antibiotic resistance plasmids have diverse transfer rates and can be spread in the absence of selection 27.03.2019 Lausanne, Switzerland Benz Fabienne;
National Research Programme 72 Meeting Poster Quantifying migration rates in structured population models with deme-dependent sampling 27.03.2019 Lausanne, Switzerland Stadler Tanja; Bonhoeffer Sebastian; Huisman Jana Sanne;
The Peter Doherty Institute for Infection and Immunity Talk given at a conference The phylodynamics of MDR plasmids and their hosts 06.03.2019 Melbourne, Australia Huisman Jana Sanne;
Deco 2019, 23rd Annual New Zealand Phylogenomics Meeting Talk given at a conference Quantifying migration rates in the presence of deme dependent sampling 10.02.2019 Napier, New Zealand Huisman Jana Sanne;
200 Anniversary of Max von Pettenkofer Talk given at a conference Towards the molecular basis of Salmonella diarrhea 06.12.2018 München, Germany Hardt Wolf-Dietrich;
IGC Symposium 2018: Microbial Eco-Evolutionary Dynamics Talk given at a conference PHENOTYPIC DELAY OF ANTIBIOTIC RESISTANCE MUTATIONS 21.10.2018 Oeiras, Portugal Bonhoeffer Sebastian;
SSM Meeting 2018 Poster Phylogenetics of bacteria and their plasmids: comparing bioinformatic approaches 28.08.2018 Lausanne, Switzerland Huisman Jana Sanne;
SSM Meeting 2018 Poster A reservoir for Salmonella conjugative plasmids in the intestinal mucosa 28.08.2018 Lausanne, Switzerland Bakkeren Erik;
Plasmid Biology 2018 Poster NN 05.08.2018 Seattle, United States of America Benz Fabienne;
D-BIOL Symposium Poster A reservoir for Salmonella conjugative plasmids in the intestinal mucosa 11.06.2018 Davos, Switzerland Bakkeren Erik;
Bacterial Persistence and Antimicrobial Therapy 2018 Talk given at a conference Clinical Manifestations of Bacterial Persistence 10.06.2018 Ascona, Switzerland Hardt Wolf-Dietrich;
ECCMID 2018 Talk given at a conference What makes pathogens emerge? The case of Salmonella Typhimurium 21.04.2018 Madrid, Spain Hardt Wolf-Dietrich;
NRP72 Poster Phylogenetics of bacteria and their plasmids: comparing bioinformatic approaches 18.04.2018 Nottwil, Switzerland Huisman Jana Sanne;
Genome Evolution 2018 Talk given at a conference Phenotypic delay of antibiotic resistance mutations 16.04.2018 Tel Aviv, Israel Bonhoeffer Sebastian;
Challenges and new concepts in antibiotics research Talk given at a conference An old challenge and some new concepts: a dynamical perspective on antibiotic resistance evolution 19.03.2018 Paris, France Bonhoeffer Sebastian;


Associated projects

Number Title Start Funding scheme
192428 The role of community-level microbial interactions in antibiotic resistance evolution 01.09.2020 Project funding (Div. I-III)
176401 Infectious disease dynamics: spread along contact networks and experimental evolution of antibiotic resistance 01.01.2018 Project funding (Div. I-III)
192567 Mechanisms controlling the Salmonella Typhimurium gut infection 01.05.2020 Project funding (Div. I-III)

Abstract

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.
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