Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance
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Type
ArticleAuthors
Phelan, JodyColl, Francesc

McNerney, Ruth

Ascher, David B.
Pires, Douglas E. V.
Furnham, Nick
Coeck, Nele
Hill-Cawthorne, Grant A.

Nair, Mridul
Mallard, Kim
Ramsay, Andrew
Campino, Susana
Hibberd, Martin L.

Pain, Arnab

Rigouts, Leen
Clark, Taane G.

KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionBioscience Program
Computational Bioscience Research Center (CBRC)
Pathogen Genomics Laboratory
Date
2016-03-23Online Publication Date
2016-03-23Print Publication Date
2016-12Permanent link to this record
http://hdl.handle.net/10754/603611
Metadata
Show full item recordAbstract
Background 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. Methods 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. Results 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. Conclusions Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management.Citation
Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance 2016, 14 (1) BMC MedicineSponsors
JP is supported by a BBSRC PhD studentship. The project was supported by the KAUST faculty baseline research fund (KAUST-BRF) to AP. The authors wish to thank members of KAUST Bioscience Core laboratory who sequenced the isolate DNA. DBA is supported by an NHMRC CJ Martin Fellowship (APP1072476). DEVP is supported by René Rachou Research Center (CPqRR/FIOCRUZ Minas). DBA and DEVP are funded by a Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG). NF is funded by a Medical Research Council Methodology Research Fellowship (MR//K020420). TGC is funded by the Medical Research Council UK (Grant no. MR/K000551/1, MR/M01360X/1, MR/N010469/1). There are no conflicts of interests.Publisher
Springer NatureJournal
BMC MedicinePubMed ID
27005572Additional Links
http://www.biomedcentral.com/1741-7015/14/31Relations
Is Supplemented By:- [Dataset]
Phelan, J., Coll, F., McNerney, R., Ascher, D., Pires, D., Furnham, N., … Taane Clark. (2016). Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance. Figshare. https://doi.org/10.6084/m9.figshare.c.3633278. DOI: 10.6084/m9.figshare.c.3633278 HANDLE: 10754/624138
ae974a485f413a2113503eed53cd6c53
10.1186/s12916-016-0575-9
Scopus Count
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