Format

Send to

Choose Destination
J Antimicrob Chemother. 2008 Jan;61(1):46-53. Epub 2007 Oct 29.

MarA-mediated overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Escherichia coli.

Author information

1
Wyeth Research, Pearl River, NY, USA. keeneyd@wyeth.com

Abstract

OBJECTIVES:

The purpose of this study was to characterize decreased susceptibility to tigecycline in clinical isolates of Escherichia coli obtained during Phase 3 clinical trials.

METHODS:

Gene expression was analysed by transcriptional profile analysis and RT-PCR. Transposon mutagenesis with IS903kan was used for selection of transposon mutants. Transposon insertions were mapped by DNA sequencing and PCR analyses. The MICs were determined by broth microdilution.

RESULTS:

Both transcriptional profile analysis and Taqman RT-PCR demonstrated increased expression levels of MarA, a transcriptional activator, and AcrAB, an RND-type efflux pump, in the strains with elevated tigecycline MICs. Transposon mutagenesis generated nine mutants, the majority of which had either marA or acrB inactivated. Sequence analysis revealed a single nucleotide insertion in the open reading frame of the marR gene in less-susceptible strains of E. coli.

CONCLUSIONS:

This study suggested that a loss of MarR functionality due to a frameshift mutation resulted in constitutive overproduction of MarA and AcrAB and, consequently, in decreased susceptibility to tigecycline in clinical isolates of E. coli.

PMID:
17967850
DOI:
10.1093/jac/dkm397
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center