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Nat Genet. 2016 May;48(5):544-51. doi: 10.1038/ng.3548. Epub 2016 Apr 11.

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

Author information

1
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
2
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
3
KwaZulu-Natal Research Institute for TB and HIV (K-RITH), Durban, South Africa.
4
Delft Bioinformatics Laboratory, Delft University of Technology, Delft, the Netherlands.
5
Center for Tuberculosis Research, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
6
Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa.
7
Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
8
Department of Epidemiology, Columbia Mailman School of Public Health, New York, New York, USA.
9
School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
10
National Health Laboratory Service, Durban, South Africa.

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.

PMID:
27064254
PMCID:
PMC4848111
DOI:
10.1038/ng.3548
[Indexed for MEDLINE]
Free PMC Article

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