SEVENTH FRAMEWORK PROGRAMME THEME

FP-HEALTH-2009-single stage 
(HEALTH-2009-2.3.1-2)

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 1^st, 2010 

Project coordinator: Dan I Andersson 

Summary

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

Problem

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.

Aim

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.

Expected results

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:

1. Generate parameter values for most of the bacterial factors we expect to be important for resistance development.

2. Generate new understanding of how different levels in the pathways leading from drug sensitivity to drug resistance and high fitness are integrated.

3. Provide the experimental knowledge required to model and perform risk assessments for the development and spread of antibiotic resistance.

4. Provide the knowledge base required to develop novel diagnostic test systems for bacteria and drugs with a high risk of resistance development.

5. Develop different approaches to measure bacterial transmission between hosts.

Potential applications

1. Generate strategies to reduce the rate of resistance of development by exploiting novel drug targets and drugs.

2. Create predictive tools for industry and regulatory agencies for pre-clinical and clinical development of novel antibiotics.

3. Perform risk assessments for the development and spread of antibiotic resistance.

4. Develop novel diagnostic test systems for bacteria and drugs with a high risk of resistance development.

List of partners and contact information

Publications

Summary 18 months report