In:
Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 55, No. 6 ( 2011-06), p. 2891-2896
Abstract:
Ethambutol (EMB) is a major component of the first-line therapy of tuberculosis. Mutations in codon 306 of embB ( embB 306) were suggested as a major resistance mechanism in clinical isolates. To directly analyze the impact of individual embB 306 mutations on EMB resistance, we used allelic exchange experiments to generate embB 306 mutants of M. tuberculosis H37Rv. The level of EMB resistance conferred by particular mutations was measured in vitro and in vivo after EMB therapy by daily gavage in a mouse model of aerogenic tuberculosis. The wild-type embB 306 ATG codon was replaced by embB 306 ATC, ATA, or GTG, respectively. All of the obtained embB 306 mutants exhibited a 2- to 4-fold increase in EMB MIC compared to the wild-type H37Rv. In vivo , the one selected embB 306 GTG mutant required a higher dose of ethambutol to restrict its growth in the lung compared to wild-type H37Rv. These experiments demonstrate that embB 306 point mutations enhance the EMB MIC in vitro to a moderate, but significant extent, and reduce the efficacy of EMB treatment in the animal model. We propose that conventional EMB susceptibility testing, in combination with embB 306 genotyping, may guide dose adjustment to avoid clinical treatment failure in these low-level resistant strains.
Type of Medium:
Online Resource
ISSN:
0066-4804
,
1098-6596
DOI:
10.1128/AAC.00007-10
Language:
English
Publisher:
American Society for Microbiology
Publication Date:
2011
detail.hit.zdb_id:
1496156-8
SSG:
12
SSG:
15,3
