SEVENTH FRAMEWORK PROGRAMME THEME
Project full title: Predicting Antibiotic Resistance
Project acronym: PAR
Funding scheme: Integrated project
EC contribution: 6,000,000 Euros
Project duration: 3 years
Start date: April 1st, 2010
End date: March 31, 2013
Project coordinator: Dan I Andersson
Antibiotic resistance represents a rapidly growing global health problem caused by the use and misuse of antibiotics and spread of resistant bacteria as well as the lack of industrial development of new antibiotics. The urgency of the resistance problem makes the development of experimental and theoretical tools and methods to understand and predict (and by inference prevent) the development of antibiotic resistance a high priority. This project aims to describe and predict the dynamics of antibiotic resistance development at the level of the drug target, the microbe and the host.. The obtained results will have general biological implications with regard to molecular evolution and bacterial adaptation, virulence and transmission. Most importantly, our results will generate strategies to reduce the rate of resistance of development
The intensive use and misuse of antibiotics have resulted in antibiotic resistance among many human pathogens and there is a growing concern that the loss of therapeutic options will present us with a post-antibiotic era where present and future medical advances are negated. Resistant bacteria dramatically reduce the possibilities of treating infections effectively and increase the risk of complications and fatal outcome for patients with severe infections. Thus, antibiotic resistance represents a major public health concern and economic problem both within EU and globally.
The main aim of this proposal is to describe and predict the dynamics of antibiotic resistance development at the level of the drug target, the microbe and the host. Presently we do not know how to reduce or reverse the development of resistance, since current knowledge about the mechanisms and evolutionary constraints that drive the emergence and survival of resistant strains is scarce. In addition, the lack of knowledge means that we do not know how the various parts of the puzzle fit together, i.e. how do we connect antibiotic use patterns --> bacterial resistance mechanisms --> bacterial physiology and fitness --> bacterial survival within a host --> bacterial spread between hosts. This project aims at generating the knowledge needed to answer this question by developing novel conceptual and experimental approaches. We will also explore several approaches both with regard to new principles for rationally choosing drug targets and drugs with minimized risk of resistance development.
Microbes and antibiotics studied
A key requirement for successfully performing the described experiments is bacterial strains that are genetically and physiologically well-defined. The applicants have generated an extensive collection of resistant mutant strains ofSalmonella typhimurium, Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium tuberculosis and other bacterial species that are well-characterized with regard to genetics and resistance mechanisms. We will use a defined set strains to perform the in vitro and in vivo experiments. Among the various antibiotic classes we will examine fluoroquinolones, beta-lactams, aminoglycosides, macrolides, deformylase inhibitors, fusidic acid and rifampicin. We expect that the results produced in this project should provide knowledge and insight of general nature applicable to virtually any combination of bacterium and resistance.
The obtained results will have general biological implications with regard to molecular evolution and bacterial adaptation. Most importantly, our results will have several medically relevant applications. The expected achievements are to:
Generate parameter values for most of the bacterial factors we expect to be important for resistance development.
Generate new understanding of how different levels in the pathways leading from drug sensitivity to drug resistance and high fitness are integrated.
Provide the experimental knowledge required to model and perform risk assessments for the development and spread of antibiotic resistance.
Provide the knowledge base required to develop novel diagnostic test systems for bacteria and drugs with a high risk of resistance development.
Develop different approaches to measure bacterial transmission between hosts.
Generate strategies to reduce the rate of resistance of development by exploiting novel drug targets and drugs.
Create predictive tools for industry and regulatory agencies for pre-clinical and clinical development of novel antibiotics.
Perform risk assessments for the development and spread of antibiotic resistance.
Develop novel diagnostic test systems for bacteria and drugs with a high risk of resistance development.
List of partners and contact information
|Uppsala University, Sweden|
Dan AnderssonDiarmaid Hughes
|Statens Seruminstitut, Denmark||Niels Frimodt-Mollerfirstname.lastname@example.org|
|Hospital Ramon y Cajal, Spain||Fernando Baquero|
|University of St Andrews, UK||Stephen Gillespieemail@example.com|
|National Center for Biotechnology, Spain|
Jose Luis MartinezJesus Blazquez
|University of Zurich, Switzerland||Erik Böttgerfirstname.lastname@example.org|
|Institut Pasteur, France||Patrice Courvalinemail@example.com|
|University of Leeds, United Kingdom||Ian Choprafirstname.lastname@example.org|
|INSERM, France||Ivan Maticemail@example.com|
|Cardiff University, United Kingdom||Timothy Walsh|
|University of Sheffield, United Kingdom||Simon Fosterfirstname.lastname@example.org|
Executive Summary of PAR project, May 2013
Ever since effective antibiotic treatment was first introduced almost seventy years ago, it has been a remarkable success story and antibiotic treatment is without a doubt the single most important medical procedure or treatment ever invented as measured by the reduction in human morbidity and mortality. However, the intensive use and misuse of antibiotics have resulted in antibiotic resistance among almost all major human pathogens, and the resulting loss of therapeutic options might generate a post-antibiotic era where present and future medical advances are negated. As resistant bacteria dramatically reduce the possibilities of treating infections effectively and increase the risk of complications and fatal outcome for patients with severe infections, it represents a major public health concern and economic problem both within EU and globally.
The scientific rationale and uniting concept for this research program was to generate knowledge to describe and predict the rate and trajectory of resistance evolution and to use this knowledge to reduce or prevent it from occurring. To this end, we developed quantitative models that captured these complex dynamics, obtained relevant values for the important parameters and validated the models by testing them in suitable in vitro and in vivo models. To obtain molecularly based and quantitative descriptions of the emergence of antibiotic resistant pathogens, we integrated three levels of bioscience: biochemistry, cell biology and population geneticsto better understand and predict the process from: biochemistry of the resistance mechanism à impact on bacterial physiology à effects on bacterial survival, persistence and transmission and bacterial ability to appear within individuals and transit. To obtain the most useful and relevant experimental knowledge possible, the above problems were addressed using a combination of in vitro studies, animal experiments and clinical studies in real-life settings. This integrative approach allowed us to obtain experimental data that is clinically relevant and addresses key important public health issues.
Except for a slight initial delay during recruitment of suitable PhD students and postdocs, the project has progressed as planned and the promised objectives, deliverables and milestones have largely been reached. The work has been performed by a group of researchers that has included 13 principal investigators and approximately 30 postdocs/researchers, PhD students and technical personnel that were partly or fully funded by PAR. Our group of researchers has had 4 major research meetings during the project period, allowing us to continuously plan and evaluate our progress, integrate the different disciplines and keep all involved people updated on the progress of the project. In addition, we have had several telephone conferences, email contacts and smaller research seminars.
The research constellation has during the project-period April 2010 to March 2013 published the following where PAR-funding has been acknowledged: 135 refereed publications (primary research publications, reviews and book chapters) and 202 presentations (poster and oral) of the obtained results at international/national meetings. In addition, our results have been presented and discussed in several other fora, including EU, EMEA, IMI and in contacts with industry. We have actively used our existing research networks to inform about our aims and results, to obtain feedback on our work and to seek new and relevant collaborations.