ANTIBIOTARGET - Molecular and functional genomic approaches to novel antibacterial target discovery

EC contribution: : € 2.171.791
Duration: : 48 months
Starting date: : 01/03/2006
Funding scheme: : Marie Curie Actions-Early-Stage Training
Keywords: : Genomics, medical microbiology, genetically modified organisms, infectious diseases, antibacterials, novel treatments
Contract/Grant agreement number: : MEST-CT-2005-020278
Project web-site: : http://antibiotarget.nottingham.ac.uk/

Background:

There is currently a European fragmentation in the research field of antibacterial drug discovery. Hence a co-operative collaborative approach is required to implement new approaches for the discovery of novel antibacterials through the establishment of a competitive early stage training programme which will deliver an increased number of appropriately trained experts with skills in the key complementary areas addressed within this proposal. The ANTIBIOTARGET project will establish an innovative research-driven training programme in state-of-the-art technologies in the fields of molecular bacterial pathogenicity, functional genomics and biological chemistry directed towards the development of novel antibacterial therapies which combat the disease-causing and natural antibiotic resistance capacity of pathogenic bacteria.

Problem:

Infectious diseases account for more than 13 million deaths a year (one in two deaths in developing countries) and are the main causes of mortality and morbidity around the world. Increasing human mobility and changing social patterns as well as the increasing number of immuno-compromised individuals as a result of ageing populations, AIDs and advances in surgery and cancer chemotherapy, have all increased the spread and risk of infection. Furthermore, the WHO has stated that "no population is more vulnerable to multi-drug resistance than those admitted to hospital wards". Consequently, the spread of antibiotic resistant bacteria in hospitals means that medical procedures once previously taken for granted may have to be abandoned with enormous impacts on morbidity and mortality.

Although antibiotics have historically been very successful, the emergence of multi-antibiotic resistant bacteria and the failure of drug discovery programmes over the last 10 years to provide new broad spectrum antibiotics with truly novel modes of action is a major threat to public health worldwide. The competitiveness of Europe in this field has been further compromised by the reduction or closure of the antibacterial drug discovery programmes of the major Pharmaceutical Companies or their transfer to the USA. This is partly because of the huge economic cost of developing an antibacterial drug when such agents rapidly succumb to resistance.

Aim:

The ANTIBIOTARGET project will establish an innovative research-driven training programme in state-of-the-art technologies in the fields of molecular bacterial pathogenicity, functional genomics and biological chemistry directed towards the development of novel antibacterial therapies which combat the disease-causing and natural antibiotic resistance capacity of pathogenic bacteria. The research project will focus on Pseudomonas aeruginosa as a model pathogen since it is an important, intrinsically resistant Gram negative bacterium responsible for high infection rates in humans within the hospital environment, has a completely sequenced genome, is highly amenable to genetic manipulation and the ANTIBIOTARGET partners are all recognized international research leaders in the molecular biology, biochemistry, genetics and pathogenicity of Pseudomonas. In addition, the ubiquitiness of this organism would make any new discoveries potentially applicable to other nosocomial pathogens. Given the major threat to human health posed by multi-antibiotic resistance, the strategies used in this project will offer not only a timely opportunity to discover new antibacterial targets but also to provide a pool of highly skilled scientists with specific expertise directed towards the discovery of novel anti-infective agents.

The aims of this project are to identify targets which are involved in promoting or regulating attachment, the biofilm life-style, virulence, and intrinsic antibiotic resistance and to develop strategies for discovering new agents which inhibit the ability of bacteria to colonize tissues, cause disease and resist conventional antibiotics.

Expected and obtained results:

Unsing P. aeruginosa as a model the expected results from this project are:

To identify, on a genome-wide basis, key genes which contribute to attachment, biofilm formation, intrinsic resistance, virulence and damage to the host.
To engineer biosensor systems that will be very valuable for the screening for novel agents which will inhibit the infection process.
To identify natural products, enzymes and small compounds which inhibit attachment, virulence, biofilm development and promote antibiotic susceptibility.
To develop large scale production of pharmaceutical products identified in this project for industrial exploitation.

Potential applications:

The ANTIBIOTARGET project will enable the scientific community working antimicrobial development to gain a better understanding of the molecular mechanisms used by P. aeruginosa to cause disease. This will enable the identification of novel targets for antimicrobials against infections caused by this organim. It will also generate a number of new biosensor systems in Pseudomonas which will be exploited for the screening of novel inhibitors of virulence factor production. Furthermore it will develop 'designer' organisms to increase the production of proteins and chemical compounds that can be used therapeutically to treat Pseudomonas infections as well as high-throughput screening methods to identify enzymes and compounds inhibiting various stages of biofilm formation by Pseudomonas. These findings will also be directly applicable to other bacteria of relevance to public health.

Coordinator:

Prof Miguel Cámara
Institute of Infection, Immunity and Inflammation
School of Molecular Medical Sciences
Centre for Biomolecular Sciences
University of Nottingham
Nottingham, UK
Tel. +44 (0) 115 951 5036
Fax +44 (0) 115 846 7951
miguel.camara@nottingham.ac.uk

European Commission