title: Molecular basis of macrolide resistance in Campylobacter: role of efflux pumps and target mutations.
abstract: BACKGROUND
  Erythromycin is the drug of choice to treat human campylobacteriosis. Campylobacter isolates exhibit two different phenotypes with regard to erythromycin resistance: high-level resistant strains (HLR) and low-level resistant strains (LLR).
  
  
  OBJECTIVE
  To study the mechanisms of resistance of Campylobacter to erythromycin, its 6-O-methyl derivative clarithromycin and the ketolide telithromycin.
  
  
  RESULTS
  We observed a cross-resistance against these three molecules but in contrast, no cross-resistance to quinolones. Analyses of LLR showed no mutation on the 23S rDNA and the presence of a drug transport system, which can be inhibited by phenylalanine arginine beta-naphthylamide (PAbetaN), an efflux-pump inhibitor. In contrast, no PAbetaN-sensitive drug transport was identified in HLR but we found mutations in the rDNA, which were responsible for decreased binding of telithromycin to purified ribosomes. We further showed that the CmeB efflux pump already described in Campylobacter is not involved in the PAbetaN-sensitive transport of telithromycin.
  
  
  CONCLUSIONS
  Mutations in the ribosome confer high-level macrolide/ketolide resistance. Low-level resistance was mediated by an efflux mechanism which is sensitive to PAbetaN. This efflux pump was selective to macrolides/ketolide and was different from the previously described Campylobacter efflux pump.
authors.affiliation: Université de la Méditerranée, Enveloppe Bactérienne, Perméabilité et Antibiotiques, EA2197, IFR48, Faculté de Médecine, 27 Bd Jean Moulin 13385, Marseille Cedex 05, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mamelli
authors.forename: Valérie
authors.initials: V
authors.lastname: Prouzet-Mauléon
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
authors.forename: Francis
authors.initials: F
authors.lastname: Mégraud
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bolla
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002167:Campylobacter / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017291:Clarithromycin / Q000494:pharmacology; D004275:DNA, Ribosomal / Q000187:drug effects / Q000235:genetics; D004151:Dipeptides / Q000494:pharmacology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics / Q000502:physiology*; D004917:Erythromycin / Q000494:pharmacology; D048628:Ketolides / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009154:Mutation
chemical_list: D000900:Anti-Bacterial Agents; D004275:DNA, Ribosomal; D004151:Dipeptides; D048628:Ketolides; D018942:Macrolides; D026901:Membrane Transport Proteins; C419365:phenylalanine arginine beta-naphthylamide; D004917:Erythromycin; D017291:Clarithromycin; C106791:telithromycin