CORDIS
EU research results

CORDIS

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Compensatory Evolution and Epistasis in Multidrug-resistant Mycobacterium tuberculosis

Project information

Grant agreement ID: 309540

Status

Closed project

  • Start date

    1 April 2013

  • End date

    31 March 2018

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 498 614

  • EU contribution

    € 1 498 614

Hosted by:

SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT

Switzerland

Objective

"Multidrug-resistant bacteria are a global threat to public health and the economy. Studies in model organisms suggest compensatory evolution and epistatic interactions between drug resistance-conferring mutations are important drivers of drug resistance. However, the relevance of these factors for the emergence and transmission of human pathogenic bacteria has not been established. To bridge the gap between laboratory experimentation and epidemiology, I propose a multidisciplinary approach focusing on Mycobacterium tuberculosis, the etiologic agent of human tuberculosis (TB). Specifically, I shall combine experimental evolution and fitness assays in vitro and in human macrophages with comparative genome sequencing, RNAseq-based transcriptomics, and population-based molecular epidemiology to:

1) Identify and characterize compensatory mutations in M. tuberculosis resistant to rifampicin, streptomycin, and ofloxacin;

2) Detect epistasis between drug resistance-conferring mutations in different strain genetic backgrounds;

3) Investigate the effect of drug resistance-conferring mutations, compensatory mutations, and their epistatic interactions on the M. tuberculosis transcriptome.

The strength of my approach lies in the integration of an experimentally tractable model system (Mycobacterium smegmatis) with targeted validation experiments in clinically relevant M. tuberculosis, and comprehensive molecular epidemiological data collected prospectively in Georgia, a country with a high-burden of multidrug-resistant TB.

Through its multidisciplinary nature, this project will simultaneously test predictions from ecological theory and experimental models, generate new insights into the biology and epidemiology of multidrug-resistant TB, and ultimately contribute to the control of one of humankind’s most important infectious diseases."
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Principal Investigator

Sebastien Gagneux (Prof.)

Host institution

SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT

Address

Socinstrasse 57
Ch-4002 Basel

Switzerland

Activity type

Research Organisations

EU Contribution

€ 1 498 614

Principal Investigator

Sebastien Gagneux (Prof.)

Administrative Contact

Stefan Mörgeli (Mr.)

Beneficiaries (1)

SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT

Switzerland

EU Contribution

€ 1 498 614

Project information

Grant agreement ID: 309540

Status

Closed project

  • Start date

    1 April 2013

  • End date

    31 March 2018

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 498 614

  • EU contribution

    € 1 498 614

Hosted by:

SCHWEIZERISCHES TROPEN- UND PUBLIC HEALTH-INSTITUT

Switzerland