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

J Antimicrob Chemother. 2008 Jan;61(1):46-53. doi: 10.1093/jac/dkm397. Epub 2007 Oct 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Outer Membrane Proteins / biosynthesis
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Proteins / biosynthesis
  • Bacterial Proteins / genetics
  • Base Sequence
  • DNA Transposable Elements / genetics
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Bacterial / drug effects*
  • Drug Resistance, Bacterial / genetics
  • Escherichia coli / drug effects
  • Escherichia coli / genetics
  • Escherichia coli / isolation & purification
  • Escherichia coli / metabolism*
  • Escherichia coli Proteins / biosynthesis
  • Escherichia coli Proteins / genetics*
  • Frameshift Mutation
  • Lipoproteins / biosynthesis
  • Lipoproteins / genetics
  • Membrane Transport Proteins / biosynthesis
  • Membrane Transport Proteins / genetics
  • Microbial Sensitivity Tests
  • Minocycline / analogs & derivatives*
  • Minocycline / pharmacology
  • Molecular Sequence Data
  • Multidrug Resistance-Associated Proteins / biosynthesis
  • Multidrug Resistance-Associated Proteins / genetics
  • Open Reading Frames
  • RNA, Bacterial / genetics
  • Tigecycline


  • AcrA protein, E coli
  • AcrB protein, E coli
  • Anti-Bacterial Agents
  • Bacterial Outer Membrane Proteins
  • Bacterial Proteins
  • DNA Transposable Elements
  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • Lipoproteins
  • MarA protein, E coli
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • RNA, Bacterial
  • multiple antibiotic resistance protein B
  • tolC protein, E coli
  • Tigecycline
  • Minocycline