The disulfide bond as a chemical tool in cyclic peptide antibiotics: engineering disulfide polymyxins and murepavadin (MURYXIN)

This project presents an innovative chemical tool to be applied to known cyclic peptide antibiotics.

The rationale of the design consists of maintaining the overall structure of the antibiotic to preserve the antibacterial activity while the presence of the chemical tool within the peptide backbone would facilitate the initial metabolization and detoxification by oxidorreductases upon eventual accumulation of the antibiotic in the kidney. The project follows a proof-of-concept scheme involving the necessary chemistry to prepare the model compounds, the in vitro and in vivo assays to assess activity and low toxicity, and estimate a therapeutic window. Finallly, tests to prove the design hypothesis and the mechanism of action at the membrane level are also proposed.

Project partners

  • Francesc Rabanal, Universitat de Barcelona, Spain (Coordinator)
  • Matilda Bäckberg, RISE Research Institutes of Sweden, Sweden
  • Pawel Baranczewski, Uppsala University, Sweden
  • Edgars Liepinsh, Latvian Institute of Organic Synthesis, Latvia
  • Timothy R Walsh, University of Oxford, United Kingdom
  • Carina Vingsbo-Lundberg, Statens Serum Institut, Denmark
  • Klaus Skovbo Jensen, CANDOR Simulation, Denmark


Antimicrobial Stewardship in Hospitals, Resistance Selection and Transfer in a One Health Context (STRESST)

The transfer of antibiotic residues and antibiotic resistant bacteria into the environment and subsequently into animal drinking water may have an effect on the transmission of resistant bacteria and their resistance genes back into the human population.

This holistic One Health view of antibiotic resistance is at the heart of our project. We want to determine if hospital wide antimicrobial stewardship implementation will reduce antibiotics and antibiotic resistant bacteria from entering the environment and if the reduction of antibiotic concentrations will lower the transfer of resistance genes within and between bacteria in the environment and in animals. We will show that hospital wastewater is a hotspot for selection of resistance and pave the way for future, targeted interventions aimed at reducing the amounts of antibiotics released into the environment even further.

Project partners

  • Adam Roberts, Liverpool School of Tropical Medicine, United Kingdom (Coordinator)
  • Andrew Singer, UK Centre for Ecology and Hydrology, United Kingdom
  • Nina Langeland, University of Bergen, Norway
  • Michael Brouwer, Wageningen Bioveterinary Research, Netherlands


Specific Targeting of Antimicrobial Resistant Strains in situ using Targeted-Antibacterial-Plasmids (STARS-TAP)

The global spread of antimicrobial resistance (AMR) among pathogenic bacteria is recognized as one of the biggest concerns in public health and a research priority in microbiology.

Drug-resistance increases exponentially for certain bacterial organisms and is becoming the main threat to human health worldwide. As a consequence, national and international authorities have emphasized the need to taking a broad, coordinated approach to develop new antimicrobial strategies to fight against drug-resistant bacteria across multiple sectors such as human health and animal health, agriculture and environment1 (i.e. ‘One health’ major challenge).

The STARS-TAP research program aims at developing an innovative non-antibiotic antibacterial methodology to specifically target AMR strains from natural bacterial communities in several ecosystems in situ. The proposed methodology is based on Targeted-Antibacterial-Plasmids (TAPs) that use DNA conjugation to deliver CRISPR/Cas systems exerting a strain-specific antibacterial activity. If successful, our research would represent a real breakthrough for clinical and environmental microbiology, and open new options for the elimination of AMR strains from various ecosystems. This unexplored and versatile strategy complementary to antibiotic treatments holds the potential to be used for preventive decolonization purposes, or even in agriculture to tackle AMR prevalence in amended soils.

Project partners

  • Christian Lesterlin, Centre National de la Recherche Scientifique, France (Coordinator)
  • Pierre Bogaerts, UCL – Université Catholique de Louvain, Belgium
  • Gregory Jubelin, French National Research Institute for Agriculture, Food and Environment, France
  • Anna Marzec-Grzadziel, Institute of Soil Science and Plant Cultivation – State Research Institute, Poland
  • William Couet, French National Institute of Health and Medical Research, France


Selecting Efficient Farm-level Antimicrobial Stewardship Interventions from a one health perspective (SEFASI)

Antimicrobial resistance (AMR) links together people, plants, animals and their environments under the One Health umbrella. In this work we will similarly link interventions aimed at AMR by considering their impact not only in terms of impact on hospitals, communities or farmers, but across all of these groups.

This is key to informing optimal intervention selection by governments in tackling AMR in the future. Our research will combine statistical analysis, mathematical simulations and economic-impact models within a single intervention assessment framework. We will bring together an interdisciplinary team of economists, mathematical modellers and veterinary scientists to apply this modelling framework to three country cases studies: England, Senegal and Denmark. All three countries are global leaders in terms of AMR data collection and intervention, providing ideal settings for intervention assessment. Our outcome will be a ranking of farm-level interventions for policymakers to assess their impact from a One Health perspective, and an insight into where more data in the future would be most beneficial, in terms of reducing uncertainty in such economic evaluations of interventions.

Project partners

  • Gwenan Knight, London School of Hygiene and Tropical Medicine, United Kingdom (Coordinator)
  • Michel Dione, International Livestock Research Institute, Senegal
  • Ana Mateus, Royal Veterinary College, United Kingdom
  • Nichola Naylor, Public Health England, United Kingdom
  • Dagim Belay, University of Copenhagen, Denmark


Phage Therapy to Reduce AMR Enterobacteria Spread from a One Health Perspective (Phage-Stop-AMR)

The spread of multi-drug resistant (MDR) bacteria in food-producing animals including broilers is a global public health concern.

Controlling growth of MDR bacteria and limiting the transmission of antimicrobial resistance genes in broilers could be an effective mitigation strategy. To counteract the spread of MDR bacteria among zoonotic pathogens in food-producing animals and reduce the risk of their transmission to humans or the environment, antibiotic use in animal husbandry has to be reduced. Bacteriophage therapy is increasingly accepted as an environmentally-friendly antimicrobial intervention strategy, effective at specifically targeting bacterial pathogens, to prevent the transmission of resistant bacteria from foods to humans and vice versa.

We use MDR Salmonella and E. coli in broilers as a model and will first select the most efficient phage combinations to specifically reduce these bacteria and MDR plasmids in broilers. Using laboratory, an experimental chicken gut model and farm-level experiments, we will then establish the efficacy of phage formulations as feed additives within a commercial farming context to reduce bacterial numbers and progressively reduce MDR plasmid carriage in broilers. We will test the effect of phage therapy on intestinal parameters of the treated broilers and also on the broiler intestinal microbiome and resistome composition. We will investigate the transmission of AMR plasmids between different enterobacteria in the broiler gut and improve on-site detection of MDR foodborne pathogens as an early warning system at farm level.

Project partners

  • Ulrich Dobrindt, Universität Münster, Germany (Coordinator)
  • Clara Marín-Orenga, Universidad Cardenal Herrera – CEU, Spain
  • Muna Anjum, Animal and Plant Health Agency, United Kingdom
  • Raul Fernandez Lopez, Universidad de Cantabria, Spain
  • Danish Malik, Loughborough University, United Kingdom
  • Annamária Szmolka, Veterinary Medical Research Institute, Hungary
  • Eliora Ron, Tel Aviv University, Israel


Phage treatment and wetland technology as intervention strategy to prevent dissemination of antibiotic resistance in surface waters (PhageLand)

PhageLand is aimed to develop a novel intervention strategy combining the low-cost and eco-friendly capacity of constructed wetlands with the specificity of bacteriophages (i.e., viruses killing bacteria) to prevent the dissemination of antibiotic resistance from wastewater into surface waters.

PhageLand will investigate the prevalence of antibiotic resistant bacterial pathogens (ARB) in low-middle income countries (LMICs) in Eastern Europe, which will be then used as targets for the development of a dedicated phage-based treatment for their specific removal from communal wastes.

In parallel, PhageLand will assess: a) the purification capacity of two reference, full-scale constructed wetlands operating in Spain and Moldova in the removal of antibiotic residues, ARB and antibiotic resistance genes; and b) the potential risk associated with the dissemination of these biological pollutants within indigenous bacterial communities and among animals inhabiting constructed wetlands.

Finally, PhageLand will develop a pilot plant to scale-up the phage-wetland combined technology to assess its performance under real environmental conditions. This proof-of-concept will be used to demonstrate the efficacy of this nature-based technology for the removal of multidrug-resistant pathogens from communal wastes and to encourage stakeholders for its implementation in wastewater treatment to prevent the dissemination of antimicrobial resistance. The PhageLand technology will be particularly useful in LMICs, where costly and power-demanding treatment plants are difficult to set up.

Project partners

  • Carles Borrego, Catalan Institute for Water Research, Spain (Coordinator)
  • Lukasz Dziewit, University of Warsaw, Poland
  • Malgorzata Grzesiuk-Bieniek, Warsaw University of Life Sciences, Poland
  • Rob Lavigne, KU Leuven, Belgium
  • Evelien Adriaenssens, Quadram Institute Bioscience, United Kingdom
  • David Weissbrodt, Delft University of Technology, Netherlands
  • Alina Ferdohleb, Nicolae Testemitanu State University of Medicine and Pharmacy, Moldova


Interventions to decrease CRE colonization and transmission between hospitals, households, communities and domesticated animals (I-CRECT)

In middle-income countries antibiotic resistance is increasing causing suffering and high mortality. In 12 Vietnamese hospitals half of patients were colonised with “superbugs” called carbapenem resistant Enterobacteriaceae, for short CRE , at admission 13% and after 2 weeks in hospital 89%.

CRE colonization cause hospital infections and high mortality. As many patients are CRE colonized at hospital discharge it can spread to the household members and out in community and environment. If CRE spreads in the community it will be very difficult to treat community infections as urinary tract infections and pneumonia, increasing treatment times, costs and mortality. It is hence important to stop the spread of CRE from hospitals to community.

In our research we will follow patients that are CRE colonised at discharge out to their households. The households will be randomized to intervention and control group. An intervention to improve hygiene and decrease unnecessary antibiotic use will be evaluated on CRE transmission in the household and to domesticated. Colistin, a last resort antibiotic for very ill patients, is often used for animals in feed as growth promoter, selecting for antibiotic resistance that boomerang back into hospitals. We will assess colistin resistance in households and animals and to targeted interventions to reduce transmission. Wastewater from hospitals will be tested for antibiotics and resistant bacteria. To check the relatedness of bacteria in humans, animals and environment resistance genes will be investigated.

Project partners

  • Håkan Hanberger, Linköping University, Sweden (Coordinator)
  • Phuc Duc Pham, Hanoi University of Public Health, Vietnam
  • Dien Minh Tran, Vietnam National Children’s Hospital/ Research Institute of Childrens Health, Vietnam
  • Yaovi Mahuton Gildas Hounmanou, University of Copenhagen, Denmark
  • Mattias Larsson, Karolinska Institutet, Sweden
  • P Velavan Thirumalaisamy, The Universitätsklinikum Tübingen, Germany
  • Flavie Goutard, Centre de coopération internationale en recherche agronomique pour le développement, France


Use of phage applications to combat MRSA at the sow-piglet interface to reduce exposure of staff and contamination of the environment (PHAGE-EX)

This project addresses the issue of occupational and environmental exposure to livestock-associated MRSA in pig farms.

Using bacterial phages, we will try to reduce the transmission of MRSA from sows to their piglets during the nursing phase. Specific phage cocktails will be designed using several phages to control MRSA on the skin of sows and in their environment. This is done to produce MRSA negative piglets in herds despite having positive sows. A reduction of MRSA in the piglets is expected to contribute to the reduction of MRSA in the whole pig production pyramid. This in turn will reduce the exposure of people working on pig farms and at slaughterhouses to this kind of MRSA. In regions with intensive pig husbandry, livestock associated MRSA may contribute substantially to the overall burden of MRSA in the hospital sector. We aim to reduce this burden.

At the same time we will study potential side effects of the use of phages in pigs on the bacterial community living on pigs, in their environment and in aerosols found in pig stables. We will study changes to this community and will also study the persistence of the bacterial phages in the bacterial community and the environment.

Finally we will model the effect of the use of the phages on the transmission of the resistant bacteria within the herds, between herds and to the public health system.

Project partners

  • Bernd-Alois Tenhagen, German Federal Institute for Risk Assessment, Germany (Coordinator)
  • Udo Jäckel, Federal Institute for Occupational Safety and Health, Germany
  • Thomas Rosendal, National Veterinary Institute, Sweden, Sweden
  • Kyrre Kausrud, Norwegian Veterinary Institute, Norway
  • Annemarie Käsbohrer, University of Veterinary Medicine, Austria


Targeted removal of ARGs and facultative pathogenic bacteria (FPB) in wastewater from AMR hotspots using modular advanced treatment solutions (HOTMATS)

The objective of the project HOTMATS is to design and demonstrate effective and compact solutions for the source-treatment of wastewater emitted from AMR hotspots.

The goal is to stop the spreading of antimicrobial resistant bacteria (ARB), antibiotic resistance genes (ARG), and other health-critical microorganisms from hotspots to the public sewage network, which currently is one of the major AMR transmission links between the three pillars of One-Health. This intervention will unburden the sewage network including wastewater treatment plants from the load of AMR, and hence reduces their release to the environment.

The capability of different treatment principles will be investigated, novel treatment units will be designed, and the destruction of ARB/ARGs in contaminated wastewater will be demonstrated. Ozone, AOP, MF, and UV-C based pilot-reactors will be developed and their effectiveness to destroy ARB/ARGs in concentrated wastewater streams will be assessed at a hospital, nursery homes, and animal facilities.

Compared to existing methods, the investigated treatment solutions are more effective, have a lower footprint, and consume less energy and resources, making them attractive options for treatment at AMR hotspots, as retrofits at old building infrastructures, and where space is limited. The socio-economy assessment including the transfer from HIC to LMIC is part of the HOTMATS project by integration partners from LMICs.

Project partners

  • Thomas Schwartz, Karlsruhe Institute of Technology, Germany (Coordinator)
  • Carsten Schwermer, Norwegian Institute for Water Research, Norway
  • Jaqphet Opintan, University of Ghana, Ghana
  • Richard Wulwa, University of Nairobi, Kenya


Interventions to control the dynamics of antimicrobial resistance from chickens through the environment (ENVIRE)

The overall objective of the project ENVIRE is to contribute to the reduction of antimicrobial resistance in broiler chickens and of the spread from chicken farms to the environment, and ultimately to humans.

We will carry out intervention studies, either as an experiment or in chicken farms. We will test, which interventions are most effective and feasible: i) Antibiotic-free raising of chickens, ii) Treatment with medicinal plants as alternative for antibiotics, iii) vaccination against the bacterium Escherichia coli, iv) Application of bacteriophages that infiltrate and destroy bacteria, v) Treatment or long storage of manure, vi) Treatment of farm effluents to remove antibiotics and their residues.

Focus will be laid on certain bacteria that are widely distributed, and on certain resistances that can harm human health (e.g. so-called ESBL). A mathematical risk assessment model will be developed and used to assess the effectiveness as well as potential synergistic effects of the interventions, to reduce human exposure via the foodborne, occupational and environmental pathways. Data already available for the participating countries will be included in the model, and new, essential data will be generated within the studies. As a result, specific as well as general interventions will be identified that have the potential to reduce AMR in chicken and in the environment of chicken farms for Europe and Tunisia. To achieve this, six working groups from Germany, France, Lithuania, Poland, and Tunisia, bundle their leading expertise for the respective issue.

Project partners

  • Roswitha Merle, Freie Universität Berlin, Germany (Coordinator)
  • Lucie Collineau, French Agency for Food, Environmental and Occupational Health & Safety, France
  • Mindaugas Malakauskas, Veterinary Academy of Lithuanian University of Health Sciences, Lithuania
  • Marta Kuzminska-Bajor, Wroclaw University of Environmental and Life Sciences, Poland
  • Wejdene Mansour, University of Sousse, Tunisia
  • Tina Kabelitz, Leibniz Institute for Agricultural Engineering and Bioeconomy, Germany