Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | 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 |
Journal | Nat Genet |
Volume | 48 |
Issue | 5 |
Pages | 544-51 |
Date Published | 2016 May |
ISSN | 1546-1718 |
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. |
URL | http://dx.doi.org/10.1038/ng.3548 |
DOI | 10.1038/ng.3548 |
Pubmed | |
Alternate Journal | Nat. Genet. |
PubMed ID | 27064254 |
PubMed Central ID | PMC4848111 |
Grant List | HHSN272200900018C / AI / NIAID NIH HHS / United States T32 HL007633 / HL / NHLBI NIH HHS / United States U19 AI051794 / AI / NIAID NIH HHS / United States T34 GM007910 / GM / NIGMS NIH HHS / United States U19 AI110818 / AI / NIAID NIH HHS / United States U01 AI069924 / AI / NIAID NIH HHS / United States |
Nat Genet DOI:10.1038/ng.3548
Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance.
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