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Putative compensatory mutations in the rpoC gene of rifampicin-resistant Mycobacterium tuberculosis are associated with ongoing transmission

de Vos, M. and Müller, B. and Borrell, S. and Black, P. and van Helden, P. and Warren, R. and Gagneux, S. and Victor, T.. (2013) Putative compensatory mutations in the rpoC gene of rifampicin-resistant Mycobacterium tuberculosis are associated with ongoing transmission. Antimicrobial agents and chemotherapy : AAC, Vol. 57, H. 2. pp. 827-832.

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Official URL: http://edoc.unibas.ch/dok/A6094327

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Abstract

Rifampicin resistance in clinical isolates of Mycobacterium tuberculosis arises primarily through the selection of bacterial variants harbouring mutations in the 81 base-pair rifampicin resistance determining region of the rpoB gene. Whilst these mutations were shown to infer a fitness-cost in the absence of antibiotic pressure, compensatory mutations in rpoA and rpoC were identified, which restore the fitness of rifampicin-resistant bacteria carrying mutations in rpoB. To investigate the epidemiological relevance of these compensatory mutations, we analysed 286 drug-resistant and 54 drug-susceptible clinical M. tuberculosis isolates from Cape Town, South Africa, a high-incidence setting of multidrug-resistant tuberculosis. Sequencing of a portion of the RpoA-RpoC interaction region of the rpoC gene revealed that 23.5% of all rifampicin-resistant isolates tested carried a non-synonymous mutation in this region. These putative compensatory mutations in rpoC were associated with transmission; as 30.8% of all rifampicin-resistant isolates with an IS6110 RFLP pattern belonging to a recognized RFLP cluster harboured putative rpoC mutations. Such mutations were present in only 9.4% of rifampicin-resistant isolates with unique RFLP patterns (p>0.01). Moreover, these putative compensatory mutations were associated with specific strain genotypes, and the rpoB S531L rifampicin resistance mutation. Among isolates harbouring this rpoB mutation, 44.1% also harboured rpoC mutations while only 4.1% of the isolates with other rpoB mutations exhibited mutations in rpoC (p>0.001). Our study supports a role for rpoC mutations in the transmission of MDR-TB, and illustrates how epistatic interactions between drug resistance-conferring mutations, compensatory mutations, and different strain genetic backgrounds might influence compensatory evolution in drug-resistant M. tuberculosis
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Tuberculosis Research (Gagneux)
UniBasel Contributors:Gagneux, Sebastien
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:American Society for Microbiology
ISSN:0066-4804
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Aug 2013 07:34
Deposited On:16 Aug 2013 07:31

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