Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance

A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identif...

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Main Authors:	Desjardins, Christopher A., Cohen, Keira A., Munsamy, Vanisha, Abeel, Thomas, Maharaj, Kashmeel, Walker, Bruce J., Shea, Terrance P., Almeida, Deepak V., Manson, Abigail L., Salazar, Alex, Padayatchi, Nesri, O’Donnell, Max R., Mlisana, Koleka P., Wortman, Jennifer, Birren, Bruce W., Grosset, Jacques, Earl, Ashlee M., Pym, Alexander S.
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848111/

id	pubmed-4848111
recordtype	oai_dc
spelling	pubmed-48481112016-10-11 Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance Desjardins, Christopher A. Cohen, Keira A. Munsamy, Vanisha Abeel, Thomas Maharaj, Kashmeel Walker, Bruce J. Shea, Terrance P. Almeida, Deepak V. Manson, Abigail L. Salazar, Alex Padayatchi, Nesri O’Donnell, Max R. Mlisana, Koleka P. Wortman, Jennifer Birren, Bruce W. Grosset, Jacques Earl, Ashlee M. Pym, Alexander S. Article A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identify novel resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss-of-function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss-of-function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted utilization of this toxic drug among patients with susceptible infections. 2016-04-11 2016-05 /pmc/articles/PMC4848111/ /pubmed/27064254 http://dx.doi.org/10.1038/ng.3548 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Desjardins, Christopher A. Cohen, Keira A. Munsamy, Vanisha Abeel, Thomas Maharaj, Kashmeel Walker, Bruce J. Shea, Terrance P. Almeida, Deepak V. Manson, Abigail L. Salazar, Alex Padayatchi, Nesri O’Donnell, Max R. Mlisana, Koleka P. Wortman, Jennifer Birren, Bruce W. Grosset, Jacques Earl, Ashlee M. Pym, Alexander S.
spellingShingle	Desjardins, Christopher A. Cohen, Keira A. Munsamy, Vanisha Abeel, Thomas Maharaj, Kashmeel Walker, Bruce J. Shea, Terrance P. Almeida, Deepak V. Manson, Abigail L. Salazar, Alex Padayatchi, Nesri O’Donnell, Max R. Mlisana, Koleka P. Wortman, Jennifer Birren, Bruce W. Grosset, Jacques Earl, Ashlee M. Pym, Alexander S. Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
author_facet	Desjardins, Christopher A. Cohen, Keira A. Munsamy, Vanisha Abeel, Thomas Maharaj, Kashmeel Walker, Bruce J. Shea, Terrance P. Almeida, Deepak V. Manson, Abigail L. Salazar, Alex Padayatchi, Nesri O’Donnell, Max R. Mlisana, Koleka P. Wortman, Jennifer Birren, Bruce W. Grosset, Jacques Earl, Ashlee M. Pym, Alexander S.
author_sort	Desjardins, Christopher A.
title	Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
title_short	Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
title_full	Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
title_fullStr	Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
title_full_unstemmed	Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
title_sort	genomic and functional analyses of mycobacterium tuberculosis strains implicate ald in d-cycloserine resistance
description	A more complete understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis is critical for prompt diagnosis and optimal treatment, particularly for toxic second-line drugs like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identify novel resistance-conferring genotypes. By combining association and correlated evolution tests with strategies for amplifying signal from rare variants, we found that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, were associated with unexplained drug resistance. Convergent evolution of this loss-of-function was observed exclusively among multidrug-resistant strains. Drug susceptibility testing established that ald loss-of-function conferred resistance to D-cycloserine, and susceptibility to the drug was partially restored by complementation of ald. Clinical strains with mutations in ald and alr exhibited increased resistance to D-cycloserine when cultured in vitro. Incorporation of D-cycloserine resistance in novel molecular diagnostics could allow for targeted utilization of this toxic drug among patients with susceptible infections.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848111/
_version_	1613572104889827328

Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance

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