Predicting cell-cell horizontal transmission of antibiotics resistance from genome and phenome (TransPred)

Resistance to antibiotics, particularly in Gram-negative bacteria, is an accelerating health crisis. Only few new antibiotics against Gram-negatives are in clinical trials and resistance also to new antibiotics is predicted to spread rapidly upon clinical introduction.

Completed project

Horizontal transmission of antibiotic resistance factors within pathogenic species, combined with the selective pressure imposed by extensive antibiotic use that favours resistant strains, explains much of the accelerating antibiotics resistance crisis.

We propose to disclose candidate drug targets controlling the horizontal cell-cell transmission of anti-microbial resistance and to predict AMR and its transmission dynamics from bacterial genome composition. We employ experimental evolution of Escherichia coli, one of the most problematic species, to experimentally identify genes controlling the plasmid transmission rates. The hope is that these will be good targets for developing drugs that slows antibiotics resistance development. We also sequence the genomes of many clinical bacterial isolates and mathematically and computationally disclose natural variants likely to affect plasmid transmission properties.

We hope that this will lay the foundations for a future personalized medicine that tailors antibiotic choice to infection such that resistance development within each patient is delayed or avoided completely.

Project partners

  • Jonas Warringer, University of Gothenburg, Sweden (Coordinator)
  • Edward Moore, University of Gothenburg, Sweden
  • Gianni Liti, University of Nice, France
  • Danesh Moradigaravand, The Wellcome Trust Sanger Institute, United Kingdom
  • Jan Michiels, University of Leuven, Belgium
  • Anne Farewell, University of Gothenburg, Sweden
  • Ville Mustonen, The Wellcome Trust Sanger Institute, United Kingdom

Project resources

Tools

The manuscript that marks the release of the genomics and phenotypic resources and their global description is in preparation. Read more: github.com/matdechiara/TransPred

Publications

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Effectiveness of infection control strategies against intra- and inter-hospital transmission of MultidruG-resistant Enterobacteriaceae – insights from a multi-level mathematical NeTwork model (EMerGE-NeT)

Multidrug-resistant Enterobacteriaceae (MDR-E) is a major public health threat in many European countries. While traditional infection control strategies primarily target the containment of intra-hospital transmission, growing evidence highlights the importance of inter-hospital patient traffic for the spread of MDR-E within healthcare systems.

Completed project

Going substantially beyond previous research, the EMerGE-NeT consortium united expertise in theoretical modelling, numerical simulation studies, epidemiology, clinical medicine, and microbiology in order to develop a generic network modelling platform, which combined inter- and intra-hospital transmission of MDR-E in a single framework.

Three interconnected work packages (WP1-3) supplemented by a management and dissemination package (WP4) belonged to the project.

  • WP1: multiple network models that reflect patient traffic within and between hospitals were designed. These models showed that there is a strong connection between hospital and community prevalence of MDR-Es and that ICUs play a tremendous role regarding the risk of infection and transmission within a hospital.
  • WP2: specific molecular studies were conducted, using a novel cutting-edge methodology of genetic sequencing. The German study found that only a small proportion of MDR-E is caused by in-hospital transmission.
  • WP3: Based on a systematic literature review, only ASPs could be identified as a promising strategy for the prevention of colonization with MDR-E.

Impact

The project helped to analyse (cost-)effectiveness of different intervention strategies within hospitals. These findings can also be applied and expanded to the current COVID-19 pandemic. Through publication of various manuscripts in international peer-reviewed journals, these findings were disseminated to the respective audience worldwide. Apart from that, the development of practical recommendations, about how these strategies can be used, is still planned. Thus, the findings will be discussed with both the German health insurance companies and the hygiene/infectiology experts of the respective clinics. As the health insurance companies are important decision-makers in the German health system, the final practical recommendations will be applicable on a national level in Germany.

Project partners

  • Rafael Mikolajcyk, Helmholtz Centre for Infection Research, Germany (Coordinator)
  • Petra Gastmeier/Axel Kola, Charité University Medicine, Germany
  • Aleksander Deptula, Nicolaus Copernicus University, Poland
  • Mirjam Kretzschmar, UMC Utrecht, Netherlands
  • Leonard Leibovici, Beilinson Hospital, Israel
  • Eduardo López Cortés, Hospital Universitario Virgen Macarena, Spain
  • Monika Piotrowska, University of Warsaw, Poland
  • Suanne Haeussler, Helmholtz Centre for Infection Research, Germany

Project resources

EMerGe-Net project website

EMerGe-Net coordinator Rafael Mikolajczyk’s profile page (in German)

EMerGe-Net partner Monika Piotrowska’s profile page

Publications

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Combating MRSA; increasing our understanding of transmission success will lead to better control of MRSA (MACOTRA)

Staphylococcus aureus is a microorganism that colonizes the skin in 10-35% of healthy individuals. Methicillin-resistant S. aureus (MRSA) is characterized by clonal spread. MRSA clones are unequally distributed across the world and different clones are dominant at different times.

Completed project

The MACOTRA project studied the interaction between MRSA, humans and the environment. We used mathematical model to gain a better understanding of MRSA dynamics.

A collection of ~300 MRSA strains was genetically characterized, highlighting antimicrobial genes possibly contributing to successful transmission. Different clones were successful in different countries, partly due to antimicrobial resistance gene carriage and antimicrobial usage. Antimicrobial resistance genes transferred easily between some isolates and we identified that bacteriophage – viruses of bacteria – were responsible. Evaluation of MRSA survival under dehydrated conditions or on a human skin mimic showed similar results for epidemic and sporadic MRSA. Survival on a dry environment could not explain success of different clones. Our study of nasal samples from volunteers showed that the bacterial composition of the nose was slightly different in S. aureus carriers compared to noncarriers. Mathematical models suggested that the established dominant clone in a particular country will be maintained as the dominant clone over time.

A main predictor of success was antimicrobial resistance, driven by antibiotic use. Other important factors for success were not identified yet. To enhance international epidemiological surveillance and subsequent data collection, we presented a proposal for harmonisation of MRSA surveillance.

Project partners

  • Margreet Vos, Erasmus MC University Medical Center, Netherlands (Coordinator)
  • Jodi Lindsay, Institute of Infection and Immunity, St George’s, University of London, United Kingdom
  • Gwenan Knight, Imperial College London, United Kingdom
  • Leo Schouls, National Institute for Public Health and the Environment (RIVM), Netherlands
  • Gerard Lina, Universite Claude Bernard Lyon 1, France

Project Resources

Tools

Publications

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A multi-scale approach to understanding the mechanisms of mobile DNA driven antimicrobial resistance transmission (JumpAR)

Antimicrobial resistance (AMR) is one of the greatest global health challenges. It spreads rapidly, constantly generating more dangerous bacteria.

Completed project

Mobile genetic elements (MGEs), segments of DNA that can move between bacterial cells, are a major route for resistance transfer in microbial communities. How often such ‘jumping genes’ move, which natural and man-made compounds influence them, and how they move at the molecular level is not understood.

In JumpAR, we surveyed MGEs in all bacteria, analysed their resistance cargos and transfer trends, and illuminated the molecular machinery that move them. Drawing on genome and metagenome sequences, we gained a global picture of the abundance and distribution of MGEs and revealed their profound impact on resistance transmission.

In a dedicated clinical study, we charted the effects of antibiotics on MGE-driven resistance spreading, and we identified human drugs and environmental compounds that can block AMR gene transfer in bacteria. We further delineated the structure and functioning of the molecular machinery, showing how MGEs build remarkably complex DNA shapes to promote insertion at diverse genomic sites, expanding gene transfer across diverse bacteria. Our collective results vastly expand knowledge on MGE-driven resistance spreading, opening doors to the development of novel strategies against resistance spreading.

JumpAR: Mechanism of AMR transmission

Project partners

  • Orsola Barabas, European Molecular Biology Laboratory, Germany (Coordinator)
  • Peer Bork, European Molecular Biology Laboratory, Germany
  • Maria Fällman, Umeå University, Sweden
  • Johan Normark, Norrlands University Hospital, Sweden
  • Gerard Wright, McMaster University, Canada

Project resources

Tools

Publications

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The impact of Host restriction of Escherichia coli on Transmission dynamics and spread of antimicrobial Resistance (HECTOR)

Bacteria are increasingly resistant to antibiotics, threatening treatment of bacterial infections. Antibiotic resistance (ABR) is encoded in the DNA of the bacteria. ABR is spreading rapidly in human and animal populations because resistant bacteria are transmitted or because bacteria can transfer DNA encoding ABR to other bacteria which then also become resistant.

Completed project

Escherichia coli (E. coli) resistant to specific antibiotics are considered a high priority risk. Transfer of such E. coli between animals, such as livestock, and humans may contribute to the spread of ABR.

The HECTOR project set out to understand if certain E. coli are adapted to certain host species (human or animal) and how this adaptation is encoded by the DNA. Through genome comparison of 1198 E. coli strains, we found which E. coli strains are associated with human host, and which parts of their DNA aid in this adaptation.

We discovered that the DNA encodes metabolic activities allowing E. coli to potentially survive better in the human gut.
In addition, we studied survival and ABR transfer of E. coli adapted to different host species, in live pigs and calves, and in laboratory experiments imitating the chicken gut. We identified E. coli strains which are better able to survive in these models than other strains. However, our findings highlight the complexity of host adaptation, as we could not identify E. coli types surviving and growing well in either model. Furthermore, we observed that transfer of DNA encoding ABR is rare in such experimental conditions.

The research of HECTOR has advanced our understanding of why some bacteria are able to spread between animal and human populations, thus contributing to the spread of ABR, and why others cannot. This can be helpful for risk assessment.

Project partners

  • Constance Schultsz, University of Amsterdam, Netherlands (Coordinator)
  • Christian Menge, Friedrich-Loeffler-Institut, Germany
  • Torsten Semmler, Robert Koch Institute, Germany
  • Roberto Marcello La Regione, University of Surrey, United Kingdom
  • Lucas Domínguez Rodríguez, Universidad Complutense de Madrid, Spain
  • Stefan Schwarz, Freie Universität Berlin, Germany
  • Ngo Thi Hoa, University of Oxford, United Kingdom

Project resources

Tools

Video

Training on antibiotic usage and resistance, Go Cong Tay District, Tien Giang, Vietnam.

Publications

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Prevention and Restriction of Antimicrobial Resistance in Pneumococci by Multi-Level Modelling (Restrict-Pneumo-AMR)

Microorganisms live in most parts of our body, including the inside of our nose. Most of the microbes are harmless and can even be beneficial to our health. However, some microbes can cause diseases – although they often go unnoticed, as our immune system can remove them before we show any symptoms.

Completed project

For example, the bacterium Streptococcus pneumoniae can cause diseases such as pneumonia and meningitis, but generally, it lives harmlessly in the nose, and is particularly common in children and the elderly. The longer the bacteria live in the nose before being killed by the immune system, the more likely they are to be transmitted to another person. The amount of time it takes for the immune system to clear the bacteria depends on various factors, such as the age of the person or the bacterium’s defense mechanism and its genetic material. A particularly important aspect is to what subtype, also known as serotype, a bacterium belongs to, which is characterized by differences in the structure of the sugar coating that surrounds the microbe. However, until now, it was not known how much each of these factors contributes.

This project provides new information for understanding the processes of evolution within the host and the mechanisms by which antibiotic treatment can influence the selection for antibiotic resistance.

Project partners

  • Stephen Bentley, The Wellcome Trust Sanger Institute, United Kingdom (Coordinator)
  • Nahuel Fittipaldi, Public Health Ontario Laboratories, Canada
  • James Kellner, University of Calgary, Canada
  • Bernd Schmeck, Philipps-University Marburg, Germany
  • Paul Turner, University of Oxford, United Kingdom
  • Tom van der Poll, Academic Medical Center University of Amsterdam, Netherlands
  • Nicolas Croucher, Imperial College London, United Kingdom

Project resources

Video

The Global Pneumococcal Sequencing (GPS) project: How can whole-genome sequencing be used to make vaccines more effective?

Publications

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Mechanisms for acquisition and transmission of successful antibiotic resistant pneumococcal clones pre- and postvaccination (PNEUMOSPREAD)

Pneumococcal infections are major contributors to morbidity and mortality world-wide, even though we have access to antibiotics and intensive care.

Completed project

Pneumococci are the major cause of common milder respiratory tract infections such as otitis and sinusitis, but also to more severe infections such as pneumonia with or without septicaemia and meningitis. Despite causing all these disease with even lethal outcome, pneumococci frequently colonize healthy children from where they may spread to susceptible individuals and cause disease. Resistance to antibiotics is emerging, threatening effective treatment.

In this project we have gained important insight into factors that affect transmission of pneumococcal strains, and into the pathogenesis of pneumococcal infections. We have unravelled factors both on the bacterial side and on the host side that are important for the spread and transmission of antimicrobial susceptible and resistant pneumococcal strains using in vitro and in vivo models. Based on this knowledge, potential novel treatment and preventive methods could be developed in the future.

Project partners

  • Birgitta Henriques Normark, Karolinska Institutet, Sweden (Coordinator)
  • Aras Kadioglu, University of Liverpool, United Kingdom
  • Tim Sparwasser, Institute for Medical Microbiology and Hygiene (IMMH), Germany
  • Jens Lagergren, KTH Royal Institute of Technology, Sweden

Publications

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Using collateral sensitivity to reverse the selection and transmission of antibiotic resistance (COLLATERALDAMAGE)

Urgent action is required to stem the apocalyptic spread of antimicrobial resistance (AMR). However, because the pace of novel drug development lags behind the evolution of novel AMR determinants, new strategies of containment are required.

Completed project

In this multinational proposal we develop a resistance-reversal strategy based on the concept of collateral sensitivity (CS). CS between a pair of antibiotics occurs when resistance to one antibiotic potentiates susceptibility to another. Thus, by exploiting CS relationships through sequential drug application, resistant strains can be specifically targeted which will reduce their frequencies in the community and arrest their transmission.

Our broad aim in this proposal is to realize the unique promise of CS-informed therapies. To do so, our work packages (WP) integrate theoretical biology, evolutionary and molecular microbiology, and in vivo modeling with a specific focus on arresting the transmission of resistant E. coli and S. pneumoniae.

The expected outcomes of the proposal are to provide pre-clinical recommendations for therapy to reduce the emergence and transmission of these two globally important bacterial pathogens and to provide a framework to develop CS-based strategies for other bacterial threats.

UiT, The Arctic University of Norway, coordinates the project and run two WPs in this JPI-EC-AMR project. One WP includes experimental work on E. coli where we test if general patterns of CS can be identified in clinical E. coli strains and how horizontal gene transfer affects these networks. The other WP aims to develop a modelling framework that furthers our understanding of sequential therapy within patients in the context of CS that is scalable to investigate transmission across patient populations.

Project partners

  • Pål Jarle Johnsen, The Arctic University of Norway, Norway (Coordinator)
  • Daniel Rozen, Leiden University, Netherlands
  • Pia Abel zur Wiesch, The Arctic University of Norway, Norway
  • Dan Andersson, Uppsala University, Sweden
  • Niels Frimodt-Møller, Rigshospitalet, Denmark

Project resources

Microbiology Research Group, The Arctic University of Norway, lead by project coordinator Pål Jarle Johnsen

Publications

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Partnership against Biofilm-associated Expression, Acquisition and Transmission of AMR (BEAT-AMR)

Reducing the risk of infection associated with medical devices and surfaces in the healthcare setting has huge public health significance.

Completed project

This risk is compounded by the emergence and persistence of multi-antibiotic resistant bacteria which is considered as one of the greatest global threats to human health. Such resistance threatens the treatment of even simple infections. However, very little is known about how bacteria develop resistance on medical surfaces within which sometimes antimicrobials have been incorporated. The key mysteries are how bacteria evolve and respond dynamically to antimicrobials on such surfaces.

We developed a publicly available, experimental workflow that allows to reproducibly grow biofilms and study their underlying resistance mechanisms. Our findings show that the combination of antimicrobials used within surfaces and antibiotics supplied systemically can have an important impact on selecting for resistance. Further, we identified new mechanisms that bacteria use to dynamically adapt to antibiotics when these bacteria grow on surfaces. One such mechanism is associated to the molecular machine that allows bacteria to swim (i.e. the flagellum). These novel antibiotic resistance mechanisms associated to surface growth and the combination effects of antimicrobial surfaces together with systemically applied antibiotics should be taken into consideration when evaluating new antimicrobial surfaces used in the healthcare setting and in medical devices.

Project partners

  • Frank Schreiber, BAM-Federal Institute for Materials Research and Testing, Germany (Coordinator)
  • Qun Zulian Ren, Empa. Materials Science  and Technology, Switzerland
  • Henny C van der Mei, University Medical Center  Groningen, Netherlands
  • Saul Faust, University Hospital Southampton, United Kingdom
  • Matthias Buhmann, Empa. Materials Science  and Technology, Switzerland
  • Henk J.  Busscher, University Medical Center  Groningen, Netherlands
  • Jeremy Webb, University of Southampton, United Kingdom

Project resources

BEAT-AMR project website

Publications

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Bridging the gap between exposure to AMR in the environment and impact to human health

Exposure to antibiotic resistant bacteria in the environment (water, soil, air) will impact human health involving complex interactions between bacteria and humans. Our network of experts, and advisors, will explore and summarize available tools and study protocols to systematically quantify environmental exposures to antibiotic resistant bacteria.

Completed project 

Guidance will be given to standardise surveillance protocols and exposure assessments in order to increase current quantitative knowledge across borders. Detection methods and modelling approaches will be outlined on how to link exposure data and epidemiological data to health impacts from antibiotic resistant bacteria. This involves quantitative exposure assessments from environmental emissions, as well as model development for carriage, excretion, colonization, horizontal gene transfer and dose-response. This will provide guidance to funding agencies and researchers on how to integrate exposure assessments and human health impact assessment into surveillance programs, funding schemes and research proposals/ projects.

Environmental transmission routes will be prioritised for future human health impact assessment studies. White papers to define a toolbox of existing approaches, best practices for study setups, and to identify research gaps will be produced by the two working groups responsible for developing guidelines and protocols for exposure assessments and human health impact assessment, respectively

Network partners

  • Ana Maria de Roda Husman, National Institute for Public Health and the Environment (RIVM), Netherlands (Coordinator)

This network includes 15 partners, please click on the following link to see complete network composition: Network composition Bridging the gap between exposure to AMR in the environment and impact to human health

Antimicrobial resistance threatens prevention and treatment of an increasing range of infections. Circulation of antibiotic resistant bacteria (ARB) in the environment (water, soil, air) may significantly contribute to human exposure. However, information on exposure to ARB from environmental sources is scarce, and little is known about the complex relationships between environmental exposure to ARB and its health impact.

With the working group set up in this project, available tools and study protocols to systematically study environmental exposures to ARB and to evaluate the associated health impact have been explored and summarized. Approaches on how to link exposure data and epidemiological data to health impacts from ARB have been described. These include quantitative exposure assessment from environmental emissions, as well as model development for carriage, excretion, colonization, horizontal gene transfer and dose-response, also including epidemiological studies. The results can serve as guidance to funding agencies and researchers on how to integrate EA and human health impact assessment (HHIA) into surveillance programs, funding schemes and research proposals/ projects.

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