期刊
NATURE GENETICS
卷 48, 期 5, 页码 544-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3548
关键词
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资金
- NIAID, NIH, US Department of Health and Human Services [HHSN272200900018C]
- IeDEA (NIH) [5U01AI069924-07]
- NHLBI [T32HL007633]
- Research Foundation-Flanders
- US Centers for Disease Control and Prevention
- [U19AI51794]
- [U19AI110818]
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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