PAR - Predicting antibiotic resistance

EC contribution: : € 6,000,000
Duration: : 36 months
Starting date: : January 2010
Funding scheme: : Large-scale integrating project (IP)
Keywords: : infectious disease, bacteria, antibiotic resistance, virulence, fitness, transmission, mathematical modelling, mutation, plasmid
Contract/Grant agreement number :: : 241476
Project web-site: : http://www.imbim.uu.se/projects/EU+project

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 (AR) development at the level of the drug target, the microbe and the host. At the present time, 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 severe 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 proposal aims at generating the knowledge needed to answer this question by developing novel conceptual and experimental approaches. In addition, we intend to explore several approaches both with regard to new principles for rationally choosing drug targets and drugs with minimized risk of resistance development.

Expected results: :

The obtained results will have general biological implications with regard to molecular evolution and bacterial adaptation, virulence and transmission. Most importantly, our results will have several medically relevant applications. The expected achievements of our objectives 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 compounds with a high risk of resistance development.
Develop and implement the use of different approaches to measure bacterial transmission between hosts.

Potential applications:

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.

Coordinator:

Dan I. Andersson
Uppsala University, Dept. of Medical Biochemistry and Microbiology, Uppsala, Sweden
Dan.Andersson@imbim.uu.se

European Commission