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Antimicrobial Agents and Chemotherapy, January 2002, p. 125-131, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.125-131.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Diversity of Ribosomal Mutations Conferring Resistance to Macrolides, Clindamycin, Streptogramin, and Telithromycin in Streptococcus pneumoniae

Annie Canu,1 Brigitte Malbruny,2 Maëlle Coquemont,2 Todd A. Davies,3 Peter C. Appelbaum,3 and Roland Leclercq2*

UFR des Sciences Pharmaceutiques,1 Service de Microbiologie, Hôpital Côte de Nacre, UFR de Médecine, Caen, France,2 Hershey Medical Center, Hershey, Pennsylvania 170333

Received 7 June 2001/ Returned for modification 17 August 2001/ Accepted 1 October 2001

Mechanisms of resistance were studied in 22 macrolide-resistant mutants selected in vitro from 5 parental strains of macrolide-susceptible Streptococcus pneumoniae by serial passage in various macrolides (T. A. Davies, B. E. Dewasse, M. R. Jacobs, and P. C. Appelbaum, Antimicrob. Agents Chemother., 44:414–417, 2000). Portions of genes encoding ribosomal proteins L22 and L4 and 23S rRNA (domains II and V) were amplified by PCR and analyzed by single-strand conformational polymorphism analysis to screen for mutations. The DNA sequences of amplicons from mutants that differed from those of parental strains by their electrophoretic migration profiles were determined. In six mutants, point mutations were detected in the L22 gene (G95D, P99Q, A93E, P91S, and G83E). The only mutant selected by telithromycin (for which the MIC increased from 0.008 to 0.25 µg/ml) contained a combination of three mutations in the L22 gene (A93E, P91S, and G83E). L22 mutations were combined with an L4 mutation (G71R) in one strain and with a 23S rRNA mutation (C2611A) in another strain. Nine other strains selected by various macrolides had A2058G (n = 1), A2058U (n = 2), A2059G (n = 1), C2610U (n = 1), and C2611U (n = 4) mutations (Escherichia coli numbering) in domain V of 23S rRNA. One mutant selected by clarithromycin and resistant to all macrolides tested (MIC, >32 µg/ml) and telithromycin (MIC, 4 µg/ml) had a single base deletion (A752) in domain II. In six remaining mutants, no mutations in L22, L4, or 23S rRNA could be detected.

* Corresponding author. Mailing address: Service de Microbiologie, CHU de Caen, Avenue Côte de Nacre, 14033 Caen cedex, France. Phone: (33) 2 31 06 45 72. Fax: (33) 2 31 06 45 73. Email: leclercq-r{at}chu-caen.fr.

Antimicrobial Agents and Chemotherapy, January 2002, p. 125-131, Vol. 46, No. 1
0066-4804/01/$04.00+0     DOI: 10.1128/AAC.46.1.125-131.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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