Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-Arabinose biosynthetic and utilization pathway genes

Hassan Safi, Subramanya Lingaraju, Anita Amin, Soyeon Kim, Marcus Jones, Michael Holmes, Michael McNeil, Scott N. Peterson, Delphi Chatterjee, Robert Fleischmann, David Alland

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

To study the evolution of drug resistance, we genetically and biochemically characterized Mycobacterium tuberculosis strains selected in vitro for ethambutol resistance. Mutations in decaprenylphosphoryl-β-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 μg/ml in a wild-Type background and to increase from 16 to 32 μg/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 μg/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.

Original languageEnglish (US)
Pages (from-to)1190-1197
Number of pages8
JournalNature genetics
Volume45
Issue number10
DOIs
StatePublished - Oct 2013

All Science Journal Classification (ASJC) codes

  • Genetics

Fingerprint Dive into the research topics of 'Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-β-D-Arabinose biosynthetic and utilization pathway genes'. Together they form a unique fingerprint.

Cite this