StaphDynamics - Functional genomic characterisation of molecular determinants for staphylococcal fitness, virulence and drug resistance
- EC contribution
- : € 2.375.000
- Duration
- : 48 months
- Starting date
- : 01/04/2006
- Funding scheme
- : Specific Targeted Research Project
- Keywords
- : Staphylococcus, epidemiology, antibiotic resistance, fitness, virulence, target identification, vaccine
- Contract/Grant agreement number
- : LSHM-CT-2006-019064
- Project web-site
- : http://www.staphdynamics.net
Background:
Staphylococcus aureus is a dangerous community- and hospital-acquired pathogen. Therefore, the spread, survival and prevalence of antibiotic resistant clones of S. aureus represent an important problem for human health. The selective pressure for antibiotic resistance is a driving force due to the massive use of such drugs throughout the world. However, the overall fitness and virulence of the bacteria is determined by their underlying genetic makeup. The traits, which determine the ability of a clone to become widespread, are largely unknown. These are likely to be multifactorial, as S. aureus is widespread in the environment due to its ability to survive outside the host and to be carried as a commensal bacterium in the human nose. It is therefore crucial to determine the key parameters required for virulence, nasal colonisation and survival in the environment in order to elucidate how these combine to produce epidemic strains. This requires a detailed knowledge of the bacterial components necessary for the above processes. The StaphDynamics partnership aims to define these bacterial components, which in themselves may form novel targets for prevention and control. Specifically, the partnership will investigate the fitness and epidemiology of resistant clones, characterise the most important clones phenotypically, and identify molecular determinants for fitness, virulence and resistance. To reach these goals, the full potential of bioinformatics, genomics, and proteomics approaches will be exploited. The StaphDynamics partnership has a proven track record in the application of these cutting-edge technologies. StaphDynamics will establish strong interactive links with the European Antimicrobial Resistance Surveillance System (EARSS) which, together with the full participation of three SME companies, will guarantee a rapid translation of fundamental research data into practical clinical applications.
Problem:
The quality of life of patients infected with antibiotic-resistant micro-organisms is dramatically decreased. Hospital stays of such patients are prolonged and infections often show very dramatic effects on the individual health situation. Moreover, infections with antibiotic resistant micro-organisms even lead to a higher morbidity in specific risk groups, such as elderly, immune-suppressed patients and children. Accordingly, the StaphDynamics programme addresses the general need for generating specific knowledge and tools to significantly enhance the quality of life of infected patients, and it contributes to meeting the societal challenge of an ageing European population. This is particularly relevant in view of the cost burden for the national health systems incurred by these untreatable bacteria. Since medical knowledge and technical standards are continuously increasing and the European population is ageing at the same time, the demand for high quality medical care is growing. Therefore, the costs for national health systems will increase even more over the next years. Supporting research in the area of antibiotic-resistance is therefore not only a response to expectations of society, but will also contribute to ensuring sustainability of the European public health systems.
Aim:
The primary aim of the StaphDynamics project is to identify important molecular determinants for fitness, virulence and drug resistance of S. aureus that may serve as future targets for drug and vaccine development and to fight staphylococcal infections. The specific technical and scientific objectives include:
- Application and further development of new methods to identify novel determinants for staphylococcal fitness, virulence and drug resistance using applied genomics, proteomics, and transcriptomics. These can be used in novel tools for strain typing and profiling.
- Characterization of the function of novel gene functions in S. aureus, which are essential for growth or critical for bacterial fitness, virulence and drug resistance.
- Validation of the role of potential bacterial virulence and fitness factors in animal models of S. aureus infections and in assays for bacterial persistence in or inactivation by human phagocytes.
- Development of novel vaccines to preclude staphylococcal infections. This will involve a SME from the Netherlands (Stichting Biomade Technology).
- Development of assay systems for a few promising novel drug targets that allow high throughput screening for inhibitory compounds. Such assays will be employed in high-throughput screenings using different compound libraries with the ultimate goal to identify a first set of new lead molecules that should give raise to new antibiotics. This will involve two SMEs from Germany (EMC Microcollections GmbH and Dr. Petry Genmedics GmbH).
- Establishment of strong interactive links with the European community behind the European Antimicrobial Resistance Surveillance System (EARSS) in order to guarantee a rapid translation of fundamental research data into practical clinical applications.
Expected and obtained results:
- Novel analytical and diagnostic tools for the characterisation of strains in order to predict their virulence and epidemic behaviour. Ongoing studies are focused on the staphylococcal cell wall proteome and the exoproteome as reservoirs for important virulence factors. This will lead to the identification of novel molecular signatures of resistant clones.
- Improved understanding of fitness and epidemiology of resistant clones. Excellent progress has been achieved in the analysis of staphylococcal resistance against important human anti-bacterial defence systems, such as lysozyme, defensins and toxic skin fatty acids. This work is rapidly filling major gaps in our knowledge about the dynamic epidemiological behaviour of drug resistant S. aureus.
- Novel targets for drug and vaccine development have been identified and are being validated in ongoing research.
- Informed strategies for combating resistant clones at the European level will be developed through strong interactive links with the European Antimicrobial Resistance Surveillance System (EARSS).
Potential applications:
The StaphDynamics programme focuses on the need to translate genome data into practical applications, both in the fields of medicine (controlling infectious disease) and biotechnology. The project has been formulated to provide innovative solutions to the three industrial StaphDynamics partners (EMC, Biomade, Genmedics). Furthermore, the partnership will create an important knowledge base needed to foster European competitiveness in the area of antibiotics research.
Coordinator:
University Medical Center Groningen (UMCG)
Department of Medical Microbiology
Hanzeplein 1
P.O. Box 30 001
9700 RB Groningen, Netherlands
Tel. +31 503 633 079
Fax +31 503 633 528
E-mail: j.m.van.dijl@med.umcg.nl
Partners:
University Tübingen
Tübingen, Germany
Prof. Jiri Doskar
Department of Genetics and Molecular Biology
Brno, Czech Republic
Prof. Simon J. Foster
University of Sheffield
Sheffield, England, UK
Prof. Dr Jörg Hacker and Dr Knut Ohlsen
Institut für Molekulare Infektionsbiologie
Würzburg, Germany
Prof. Dr Michael Hecker and Dr Susanne Engelmann
Ernst-Moritz-Arndt Universität
Greifswald, Germany
Dr Iñigo Lasa
Universidad Publica de Navarra / Consejo Superior de Investigaciones Científicas
Pamplona, Spain
Prof. Tarek Msadek
Institut Pasteur
Paris, France
Prof. Hajo Grundmann
European Antimicrobial Resistance Surveillance System
Bilthoven, Netherlands
Dr Karl-Heinz Wiesmüller and Dr Renate Spohn
EMC microcollections GmbH
Tübingen, Germany
Dr Tjibbe Bosma
Biomade Technology
Groningen, Netherlands
Dr Carolin Petry
Genmedics GmbH
Tübingen, Germany