micro-MATRIX - micro-MATRIX: Workshop on strategies to address antimicrobial resistance through the exploitation of microbial genomics

EC contribution: : € 34.002
Duration: : 09 months
Starting date: : 01/01/2004
Funding scheme: : Specific Support Action
Keywords: : bacteria, essential functions, regulation, gene expression, stress response, pathogenesis, genome, interactome, resistome
Contract/Grant agreement number: : LSSM-CT-2003-502801
Project web-site: :
For the book of abstracts:
www.cnb.csic.es/~mvicente/full_book.pdf
For the final report:
www.cnb.csic.es/~mvicente/micro-MATRIX+cover.pdf

Background:

Recent genomic technologies allow the study of global physiological processes in microbes. Their application to the study of pathogens allows to search for new medicines to combat infection and to better avoid the emergence of resistance against them. It will also help to anticipate therapies for new emerging diseases and to devise treatments to help individual patients to overcome each infection. Predictive Microbiology, based on genomic analysis, may also be used to anticipate the presence of unexpected potential pathogens. Both industrial and sustained public sector efforts are needed to fully develop the promising potential of this research frontier of the microbial world.

Problem:

The ability to effectively treat microbial infections will reduce morbidity, and have a positive impact on health management policies. The discovery of new antibacterial agents against resistant micro-organisms is an urgent and vital need. The social costs incurred by the incidence of infectious diseases in the population at large, and in particular the elderly and the productive age sectors, are enormous. Hospitalisation costs per patient run above about 500 € per day. Curbing the spread of resistant pathogens will result in the attainment of high standards in human health care, it will reduce social and public healthcare costs and will therefore have a beneficial impact on the citizens.

Aim:

To discuss microbial functional genomics as a powerful and innovative tool to discover new cellular targets that will be used to counteract bacterial resistance to antibiotics and to further avoid the generation and spread of new resistances.

Expected and obtained results:

The workshop conclusions were summarised in a report
(http://www.cnb.csic.es/~mvicente/micro-MATRIX+cover.pdf) submitted to the European Commission. It provided a roadmap to implement a research activity based on functional genomics to tackle the problem of antibiotic resistance and discovery.

A summary of the report was presented at the PathoGenoMics ERA-NET Constituent Assembly that took place in Berlin on 14th October 2004 with the purpose of coordinating research to improve understanding of pathogenic microorganisms and thus to design better treatments to curb infections..

Two reseach projects were designed as a result of collaborations initiated at the Workshop: Eureka Σ!3554-DEADBUGS, wich aims at developping new antimicrobial drugs to inhibit the bacterial two component systems. Coordinated by SALVAT S.A. (Teresa Pellicer) and including research groups at CSIC (Paloma López) and University of Amsterdam (Jerry Wells). MYCOMANCY LSHP-CT-2006-037566, to study latency in Mycobacterium tuberculosis. Coordinated by the University of Padova (Riccardo Manganelli) with participation among others of CSIC (Miguel Vicente)

A review paper authored by several participants in the micro-MATRIX workshop was published: M. Vicente, J. Hodgson, O. Massidda, T. Tonjum, B. Henriques-Normark, and E. Z. Ron. 2006. The Fallacies of Hope: will we discover new antibiotics to combat pathogenic bacteria in time? FEMS Microbiol. Rev. 30: 841-852.

Potential applications:

How Genomics can help to combat antibiotic resistance?

Genomics has been applied to identify new inhibitable bacterial targets, but it can be used as well to gain valuable knowledge on how bacteria behave during infection, how they respond when their proliferation is challenged or when they are treated with an antibiotic.

Comparative genomics in target identification

Comparative genomics yields information on the universality of targets in important pathogens. Moreover, it identifies those genes, that being absent in humans and animals are less likely to produce problems when their function is blocked. A search comparing the genomes of three important pathogens, Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus indicated that more than 350 bacterial genes are possible targets (Payne, D. J. Microbiology today, 2004, 31: 55-57).

Functional genomics in target identification

Genomics can help to refine and validate targets by analysing changes in the expression of genes that take place in the microbes when they are subject to stressful conditions that mimic the environment confronted during the process of infection. Progress in molecular modelling and in the synthetic skills needed for mimicking protein surfaces will allow the exploitation of the interactome (the set of molecular interactions within a biological system) by identifying the interactions required for the survival of the pathogen and for its interaction with the host.

How to avoid the path to resistance

Functional Genomics supplies data on how bacteria respond to different environments by adjusting the rates at which different genes are transcribed. Obtaining a global picture of the changes that occur in bacteria when they are treated with an antibiotic lead will serve to predict the likelihood of resistance emergence before the lead is further developed into a medicine. This will save efforts on compounds that are prone to elicit resistance and will provide information on how to anticipate resistance and devise procedures to circumvent it before a new antibiotic is in clinical use. Identification of the resistome (the pool of resistance genes in a particular environment) will also help to anticipate resistance to new antimicrobials.

Genomics of the antibiotic producers

Genomic research when applied to describe the global regulatory circuits in the antibiotic-producing organisms, in particular under suboptimal and stressful conditions, will help to modify the production of some secondary metabolites without greatly disturbing growth. This will increase the amount of antibiotic produced by the producer organisms.

Diagnostics

DNA arrays can speed up the diagnosis of infections. Moreover the use of subgenomic arrays, containing suitable sets of genes will easily identify specific strains of a pathogen. Once the technology is fully developed it will be possible to design antibiotic courses specifically tailored to help an individual patient to fight against one particular infection.

Coordinator:

Prof. Miguel Vicente
Centro Nacional de Biotecnología CSIC
Darwin 3, Campus de Cantoblanco
28049 Madrid, Spain
E-mail: mvicente@cnb.uam.es

European Commission