Evolution of high-level ethambutol-resistant tuberculosis through interacting mutations in decaprenylphosphoryl-ß-D-arabinose biosynthetic and utilization pathway genes.
Nat Genet
; 45(10): 1190-7, 2013 Oct.
Article
en En
| MEDLINE
| ID: mdl-23995136
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-ß-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Arabinosa
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Farmacorresistencia Microbiana
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Evolución Molecular
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Etambutol
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Mutación
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Mycobacterium tuberculosis
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Antituberculosos
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos