Journal
NATURE GENETICS
Volume 45, Issue 10, Pages 1190-U330Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2743
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Funding
- National Institute of Allergy and Infectious Diseases, US National Institutes of Health [AI080653, AI065663, AI037139]
- Pathogen Functional Genomics Resource Center [N01-AI5447]
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To study the evolution of drug resistance, we genetically and biochemically characterized Mycobacterium tuberculosis strains selected in vitro for ethambutol resistance. Mutations in decaprenylphosphoryl-beta-D-arabinose (DPA) biosynthetic and utilization pathway genes Rv3806c, Rv3792, embB and embC accumulated to produce a wide range of ethambutol minimal inhibitory concentrations (MICs) that depended on mutation type and number. Rv3806c mutations increased DPA synthesis, causing MICs to double from 2 to 4 mu g/ml in a wild-type background and to increase from 16 to 32 mu g/ml in an embB codon 306 mutant background. Synonymous mutations in Rv3792 increased the expression of downstream embC, an ethambutol target, resulting in MICs of 8 mu g/ml. Multistep selection was required for high-level resistance. Mutations in embC or very high embC expression were observed at the highest resistance level. In clinical isolates, Rv3806c mutations were associated with high-level resistance and had multiplicative effects with embB mutations on MICs. Ethambutol resistance is acquired through the acquisition of mutations that interact in complex ways to produce a range of MICs, from those falling below breakpoint values to ones representing high-level resistance.
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