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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- medical and health scienceshealth sciencespublic healthepidemiology
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistance
- medical and health sciencesclinical medicinepneumologytuberculosis
- natural sciencesbiological sciencesgeneticsmutation
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Call for proposal
ERC-2012-StG_20111109
See other projects for this call
Funding Scheme
ERC-SG - ERC Starting GrantHost institution
4123 Allschwil
Switzerland