Molecular basis of macrolide resistance in Campylobacter: role of efflux pumps and target mutations.
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.
Mamelli
Laurent
L
Université de la Méditerranée, Enveloppe Bactérienne, Perméabilité et Antibiotiques, EA2197, IFR48, Faculté de Médecine, 27 Bd Jean Moulin 13385, Marseille Cedex 05, France.
Prouzet-Mauléon
Valérie
V
Pagès
Jean-Marie
JM
Mégraud
Francis
F
Bolla
Jean-Michel
JM
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
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