Clinically relevant mutations that cause derepression of the Neisseria gonorrhoeae MtrC-MtrD-MtrE Efflux pump system confer different levels of antimicrobial resistance and in vivo fitness

Mol Microbiol. 2008 Oct;70(2):462-78. doi: 10.1111/j.1365-2958.2008.06424.x. Epub 2008 Aug 27.


The MtrC-MtrD-MtrE efflux pump system confers resistance to macrolide antibiotics and antimicrobial substances of the host innate defence. Clinical isolates with increased resistance to erythromycin and azithromycin frequently harbour mutations in the mtrR structural gene, which encodes a repressor of the mtrCDE operon, or the mtrR promoter region. The MtrC-MtrD-MtrE system is important for gonococcal survival in the murine genital tract, and derepression of the mtrCDE operon via deletion of mtrR confers increased fitness in vivo. Here we compared isogenic strains with naturally occurring mtrR locus mutations for differences in mtrCDE expression and pump-related phenotypes. Mutations upstream of mtrC, including those within the MtrR binding region and a novel mutation that increases mtrC RNA stability conferred the highest levels of derepression as measured by mtrCDE transcription and resistance to antibiotics, progesterone and antimicrobial peptides. In contrast, mutations within the mtrR coding sequence conferred low to intermediate levels of derepression. In vivo, the mtr mutants were more fit than the wild-type strain, the degree to which paralleled in vitro resistance gradients. These studies establish a hierarchy of mtrR locus mutations with regard to regulation of pump efflux, and suggest selection for more derepressed mutants may occur during mixed infections.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / pharmacology
  • Azithromycin / pharmacology
  • Bacterial Outer Membrane Proteins / biosynthesis*
  • Bacterial Proteins / biosynthesis*
  • Bacterial Proteins / genetics
  • Drug Resistance, Bacterial*
  • Erythromycin / pharmacology
  • Female
  • Gene Expression Profiling
  • Gonorrhea
  • Lipoproteins / biosynthesis*
  • Membrane Proteins / biosynthesis*
  • Membrane Transport Proteins / biosynthesis*
  • Mice
  • Mice, Inbred BALB C
  • Mutation*
  • Neisseria gonorrhoeae / drug effects*
  • Neisseria gonorrhoeae / genetics
  • Neisseria gonorrhoeae / pathogenicity*
  • Progesterone / pharmacology
  • Promoter Regions, Genetic
  • RNA Stability
  • Repressor Proteins / genetics
  • Virulence


  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Outer Membrane Proteins
  • Bacterial Proteins
  • Lipoproteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • MtrC protein, Neisseria gonorrhoeae
  • MtrD protein, Neisseria gonorrhoeae
  • MtrE protein, Neisseria gonorrhoeae
  • Repressor Proteins
  • mtrR protein, Neisseria gonorrhoeae
  • Progesterone
  • Erythromycin
  • Azithromycin