Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
| Autor: | Christopher A. Desjardins, Ashlee M. Earl, Vanisha Munsamy, Bruce J. Walker, Alexander S. Pym, Keira A. Cohen, Bruce W. Birren, Koleka Mlisana, Max R. O'Donnell, Thomas Abeel, Terrance Shea, Jennifer R. Wortman, Jacques H. Grosset, Kashmeel Maharaj, Alex N. Salazar, Deepak V. Almeida, Nesri Padayatchi, Abigail L. Manson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Tuberculosis medicine.drug_class Antibiotics Antitubercular Agents Microbial Sensitivity Tests Drug resistance Article Mycobacterium tuberculosis Gene Knockout Techniques 03 medical and health sciences Molecular genetics Drug Resistance Bacterial Genetics medicine Antibiotics Antitubercular biology Alanine Racemase Molecular diagnostics biology.organism_classification medicine.disease 3. Good health Complementation Multiple drug resistance 030104 developmental biology Alanine Dehydrogenase Cycloserine Mutation Genome Bacterial |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| DOI: | 10.1038/ng.3548 |
| Popis: | 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 like D-cycloserine. Here, we used whole-genome sequences from 498 strains of M. tuberculosis to identify novel 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 utilization of this toxic drug among patients with susceptible infections. |
| Databáze: | OpenAIRE |
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