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Characterisation of Mycobacterium Tuberculosis Populations During Infection: A  Longitudinal Study on Drug Resistance Development
Framework programme:
Project number:
EC contribution:
€ 1 050 000
36 months
Starting date:
1 December 2002

Keywords: Tuberculosis; resistance; multidrug resistance; molecular typing; MDR-TB; SNP; single nucleotide polymorphisms


Drug resistance arises in Mycobacterium tuberculosis (MTB) generally by mutation of chromosomal genes, but despite combined drug therapy, the spread of multidrug-resistant (MDR) strains is increasing alarmingly. The LONG-DRUG project is a longitudinal study, carried out in an area with high MDR-TB prevalence, which aims to document the generation of multidrug resistant MTB strains through the use of novel molecular techniques. The combined use of a variety of techniques on longitudinally obtained samples and primary cultures will enable clinically significant knowledge to be generated on the evolution of multidrug resistance in Mycobacterium.

MTB positive clinical samples will be collected in the central TB Hospital of Abkhazia (former Soviet Union), an area of increased MDR-TB prevalence, by Médecins Sans Frontières (MSF). An already ongoing medical aid programme of MSF is a guarantee for longitudinal sample collection. After sample shipment and routine microbiological examination, the minimal inhibitory concentration to primary and secondary anti-tuberculosis drugs will be determined. The determination of the resistance phenotype will target the qualitative molecular analysis to resistance-related genes. Real time PCR and RFLP-PCR will be used to screen for heterogeneous MTB populations. Quantitative real time PCR using molecular beacons on sequenced single nucleotide polymorphisms will finally elucidate prevalence of single resistant clones in bacterial populations. The genetic relationship of all significant strains will be analysed by IS-RFLP and spoligotyping. Centralised data management and correlation of clinical, bacteriological and molecular data should enable elucidation of the contribution of resistant subpopulations to the development of MDR-TB and thus the clinical significance of drug-resistant TB clones in mixed populations.


High prevalence of drug resistance in TB in various geographical settings suggests that MDR-TB may become a more significant problem in the future, even for industrialised countries. The fact that no significant novel first line anti-TB drugs have been developed over the last 40 years does contribute to the significance of the problem.

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