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Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis

Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences of polymorphism within these candidate loci remain poorly understood. To address this, we have used computational tools to quantify the...

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Autores principales: Portelli, Stephanie, Phelan, Jody E., Ascher, David B., Clark, Taane G., Furnham, Nicholas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193939/
https://www.ncbi.nlm.nih.gov/pubmed/30337649
http://dx.doi.org/10.1038/s41598-018-33370-6
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author Portelli, Stephanie
Phelan, Jody E.
Ascher, David B.
Clark, Taane G.
Furnham, Nicholas
author_facet Portelli, Stephanie
Phelan, Jody E.
Ascher, David B.
Clark, Taane G.
Furnham, Nicholas
author_sort Portelli, Stephanie
collection PubMed
description Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences of polymorphism within these candidate loci remain poorly understood. To address this, we have used computational tools to quantify the effects of point mutations conferring resistance to three major anti-tuberculosis drugs, isoniazid (n = 189), rifampicin (n = 201) and D-cycloserine (n = 48), within their primary targets, katG, rpoB, and alr. Notably, mild biophysical effects brought about by high incidence mutations were considered more tolerable, while different structural effects brought about by haplotype combinations reflected differences in their functional importance. Additionally, highly destabilising mutations such as alr Y388, highlighted a functional importance of the wildtype residue. Our qualitative analysis enabled us to relate resistance mutations onto a theoretical landscape linking enthalpic changes with phenotype. Such insights will aid the development of new resistance-resistant drugs and, via an integration into predictive tools, in pathogen surveillance.
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spelling pubmed-61939392018-10-23 Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis Portelli, Stephanie Phelan, Jody E. Ascher, David B. Clark, Taane G. Furnham, Nicholas Sci Rep Article Genomic studies of Mycobacterium tuberculosis bacteria have revealed loci associated with resistance to anti-tuberculosis drugs. However, the molecular consequences of polymorphism within these candidate loci remain poorly understood. To address this, we have used computational tools to quantify the effects of point mutations conferring resistance to three major anti-tuberculosis drugs, isoniazid (n = 189), rifampicin (n = 201) and D-cycloserine (n = 48), within their primary targets, katG, rpoB, and alr. Notably, mild biophysical effects brought about by high incidence mutations were considered more tolerable, while different structural effects brought about by haplotype combinations reflected differences in their functional importance. Additionally, highly destabilising mutations such as alr Y388, highlighted a functional importance of the wildtype residue. Our qualitative analysis enabled us to relate resistance mutations onto a theoretical landscape linking enthalpic changes with phenotype. Such insights will aid the development of new resistance-resistant drugs and, via an integration into predictive tools, in pathogen surveillance. Nature Publishing Group UK 2018-10-18 /pmc/articles/PMC6193939/ /pubmed/30337649 http://dx.doi.org/10.1038/s41598-018-33370-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Portelli, Stephanie
Phelan, Jody E.
Ascher, David B.
Clark, Taane G.
Furnham, Nicholas
Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
title Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
title_full Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
title_fullStr Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
title_full_unstemmed Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
title_short Understanding molecular consequences of putative drug resistant mutations in Mycobacterium tuberculosis
title_sort understanding molecular consequences of putative drug resistant mutations in mycobacterium tuberculosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193939/
https://www.ncbi.nlm.nih.gov/pubmed/30337649
http://dx.doi.org/10.1038/s41598-018-33370-6
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