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

Journal article (2016)

Authors

CA Desjardins Massachusetts Institute of Technology
KA Cohen Massachusetts Institute of Technology
undefined More Authors More Authors External organisation
V Munsamy KwaZulu-Natal Research Institute for TB and HIV
T.E.P.M.F. Abeel Pattern Recognition and Bioinformatics - EEMCS
K Maharaj KwaZulu-Natal Research Institute for TB and HIV
Bruce J. Walker Massachusetts Institute of Technology
Terrance Shea Massachusetts Institute of Technology
DV Almeida KwaZulu-Natal Research Institute for TB and HIV
Abigail L. Manson Massachusetts Institute of Technology
A.N. Salazar Massachusetts Institute of Technology, Pattern Recognition and Bioinformatics - EEMCS
Research Group
Pattern Recognition and Bioinformatics (EEMCS) (TU Delft)
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Published Date

2016

Language

English

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Faculty

Electrical Engineering, Mathematics and Computer Science

Department

Intelligent Systems

Research Group

Pattern Recognition and Bioinformatics

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.