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Antimicrobial Agents and Chemotherapy, July 2002, p. 2200-2207, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2200-2207.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Resistance to Quinupristin-Dalfopristin Due to Mutation of L22 Ribosomal Protein in Staphylococcus aureus

Brigitte Malbruny,1 Annie Canu,2 Bülent Bozdogan,1 Bruno Fantin,3 Virginie Zarrouk,3 Sylvie Dutka-Malen,4 Celine Feger,4 and Roland Leclercq1*

Service de Microbiologie, CHU de Caen,1 UFR Pharmacie, Caen,2 INSERM EMI9933 and Bichat University, Paris,3 Anti-Infective Clinical Research, Aventis, Vitry-sur-Seine, France4

Received 29 October 2001/ Returned for modification 19 February 2002/ Accepted 3 April 2002

The mechanism of resistance to the streptogramin antibiotics quinupristin and dalfopristin was studied in a Staphylococcus aureus clinical isolate selected under quinupristin-dalfopristin therapy, in four derivatives of S. aureus RN4220 selected in vitro, and in a mutant selected in a model of rabbit aortic endocarditis. For all strains the MICs of erythromycin, quinupristin, and quinupristin-dalfopristin were higher than those for the parental strains but the MICs of dalfopristin and lincomycin were similar. Portions of genes for domains II and V of 23S rRNA and the genes for ribosomal proteins L4 and L22 were amplified and sequenced. All mutants contained insertions or deletions in a protruding ß hairpin that is part of the conserved C terminus of the L22 protein and that interacts with 23S rRNA. Susceptible S. aureus RN4220 was transformed with plasmid DNA encoding the L22 alteration, resulting in transformants that were erythromycin and quinupristin resistant. Synergistic ribosomal binding of streptogramins A and B, studied by analyzing the fluorescence kinetics of pristinamycin IA-ribosome complexes, was abolished in the mutant strain, providing an explanation for quinupristin-dalfopristin resistance.

* Corresponding author. Mailing address: CHU de Caen, Service de Microbiologie, Avenue Côte de Nacre, 14033 Caen Cedex, France. Phone: (33) 02 31 06 45 72. Fax: (33) 02 31 06 45 73. E-mail: leclercq-r{at}chu-caen.fr.

Antimicrobial Agents and Chemotherapy, July 2002, p. 2200-2207, Vol. 46, No. 7
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.7.2200-2207.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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