Whole genome sequences for M.tuberculosis isolates from the TDR strain bank

Phelan, JORCID logo, Coll, FORCID logo, Mcnerney, R, Ascher, DB, Pires, DEV, Furnham, NORCID logo, Coeck, N, Hill-Cawthorne, GA, Nair, MB, Mallard, K, Ramsay, A, Campino, SORCID logo, Hibberd, MORCID logo, Pain, A, Rigouts, L and Clark, TORCID logo (2015). Whole genome sequences for M.tuberculosis isolates from the TDR strain bank. [Dataset]. European Nucleotide Archive. http://www.ebi.ac.uk/ena/data/view/PRJEB11653
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Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance. To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods. The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites.

Keywords

Tuberculosis, Drug resistance, Genomics, Protein structural modelling, Association study, Convergent evolution

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The isolates according to geographic location and phenotypic drug resistance
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