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Nat Genet DOI:10.1038/ng.3548

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

Publication TypeJournal Article
Year of Publication2016
AuthorsDesjardins, 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
JournalNat Genet
Date Published2016 May

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.


Alternate JournalNat. Genet.
PubMed ID27064254
PubMed Central IDPMC4848111
Grant ListHHSN272200900018C / 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