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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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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

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

David Keeney1,*, Alexey Ruzin1, Fionnuala McAleese2, Ellen Murphy3 and Patricia A. Bradford1

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{phi}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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