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

Christopher A. Desjardins; Keira A. Cohen; Vanisha Munsamy; Thomas Abeel; Kashmeel Maharaj; Bruce J. Walker; Terrance P. Shea; Deepak V. Almeida; Abigail L. Manson; Alex Salazar; Nesri Padayatchi; Max R. O'Donnell; Koleka P. Mlisana; Jennifer Wortman; Bruce W. Birren; Jacques Grosset; Ashlee M. Earl; Alexander S. Pym

doi:10.1038/ng.3548

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

Christopher A. Desjardins, Keira A. Cohen, Vanisha Munsamy, Thomas Abeel, Kashmeel Maharaj, Bruce J. Walker, Terrance P. Shea, Deepak V. Almeida, Abigail L. Manson, Alex Salazar, Nesri Padayatchi, Max R. O'Donnell, Koleka P. Mlisana, Jennifer Wortman, Bruce W. Birren, Jacques Grosset, Ashlee M. Earl, Alexander S. Pym

School of Medicine

Research output: Contribution to journal › Article › peer-review

88 Scopus citations

Abstract

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 such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new 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 use of this toxic drug among patients with susceptible infections.

Original language	English (US)
Pages (from-to)	544-551
Number of pages	8
Journal	Nature genetics
Volume	48
Issue number	5
DOIs	https://doi.org/10.1038/ng.3548
State	Published - May 1 2016

ASJC Scopus subject areas

Genetics

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Desjardins, C. A., Cohen, K. A., Munsamy, V., Abeel, T., Maharaj, K., Walker, B. J., Shea, T. P., Almeida, D. V., Manson, A. L., Salazar, A., Padayatchi, N., O'Donnell, M. R., Mlisana, K. P., Wortman, J., Birren, B. W., Grosset, J., Earl, A. M., & Pym, A. S. (2016). Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance. Nature genetics, 48(5), 544-551. https://doi.org/10.1038/ng.3548

Desjardins, CA, Cohen, KA, Munsamy, V, Abeel, T, Maharaj, K, Walker, BJ, Shea, TP, Almeida, DV, Manson, AL, Salazar, A, Padayatchi, N, O'Donnell, MR, Mlisana, KP, Wortman, J, Birren, BW, Grosset, J, Earl, AM & Pym, AS 2016, 'Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance', Nature genetics, vol. 48, no. 5, pp. 544-551. https://doi.org/10.1038/ng.3548

@article{73a555f09d194d8c8673ece5a4844463,

title = "Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance",

abstract = "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 such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new 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 use of this toxic drug among patients with susceptible infections.",

author = "Desjardins, {Christopher A.} and Cohen, {Keira A.} and Vanisha Munsamy and Thomas Abeel and Kashmeel Maharaj and Walker, {Bruce J.} and Shea, {Terrance P.} and Almeida, {Deepak V.} and Manson, {Abigail L.} and Alex Salazar and Nesri Padayatchi and O'Donnell, {Max R.} and Mlisana, {Koleka P.} and Jennifer Wortman and Birren, {Bruce W.} and Jacques Grosset and Earl, {Ashlee M.} and Pym, {Alexander S.}",

note = "Funding Information: This project has been funded in part with federal funds from NIAID, NIH, US Department of Health and Human Services, under contract HHSN272200900018C, IeDEA (NIH grant 5U01AI069924-07), and grant U19AI110818 to the Broad Institute. K.A.C. was supported by NHLBI grant T32HL007633. T.A. was supported by a postdoctoral fellowship from the Research Foundation-Flanders. Additional funding sources included grant U19AI51794 and the US Centers for Disease Control and Prevention. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

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AU - Desjardins, Christopher A.

AU - Cohen, Keira A.

AU - Munsamy, Vanisha

AU - Abeel, Thomas

AU - Maharaj, Kashmeel

AU - Walker, Bruce J.

AU - Shea, Terrance P.

AU - Almeida, Deepak V.

AU - Manson, Abigail L.

AU - Salazar, Alex

AU - Padayatchi, Nesri

AU - O'Donnell, Max R.

AU - Mlisana, Koleka P.

AU - Wortman, Jennifer

AU - Birren, Bruce W.

AU - Grosset, Jacques

AU - Earl, Ashlee M.

AU - Pym, Alexander S.

N1 - Funding Information: This project has been funded in part with federal funds from NIAID, NIH, US Department of Health and Human Services, under contract HHSN272200900018C, IeDEA (NIH grant 5U01AI069924-07), and grant U19AI110818 to the Broad Institute. K.A.C. was supported by NHLBI grant T32HL007633. T.A. was supported by a postdoctoral fellowship from the Research Foundation-Flanders. Additional funding sources included grant U19AI51794 and the US Centers for Disease Control and Prevention. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Publisher Copyright: © 2016 Nature America, Inc.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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 such as D-cycloserine. Here we used the whole-genome sequences from 498 strains of M. tuberculosis to identify new 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 use of this toxic drug among patients with susceptible infections.

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

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