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