JAC Advance Access originally published online on October 29, 2007
Journal of Antimicrobial Chemotherapy 2008 61(1):46-53; doi:10.1093/jac/dkm397
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Original research |
MarA-mediated overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Escherichia coli
1 Wyeth Research, Pearl River, NY, USA 2 Wyeth Research, Cambridge, MA, USA 3 Wyeth Vaccines, Pearl River, NY, USA
Received 15 June 2007; returned 20 August 2007; revised 12 September 2007; accepted 24 September 2007
* Corresponding author. Tel: +1-845-602-8360; Fax: +1-845-602-5671; E-mail: keeneyd{at}wyeth.com
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 IS903
kan 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.
Keywords: resistance nodulation cell division family , antibiotic resistance , multidrug efflux pump , RT-PCR , transcriptional profile analysis
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