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JAC Advance Access published online on August 13, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg348
© 2003 by The British Society for Antimicrobial Chemotherapy
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© 2003 The British Society for Antimicrobial Chemotherapy

Original article

High-level telithromycin resistance in laboratory-generated mutants of Streptococcus pneumoniae

Fiona Walsh 1 *, Joanne Willcock 2 , and Sebastian Amyes 1

1 Department of Medical Microbiology, Medical School, University of Edinburgh, Edinburgh EH8 9AG
2 Aventis Pharma Ltd., Kings Hill, West Malling, Kent ME19 4 AH, UK

* Corresponding author. E-mail: fwalsh{at}staffmail.ed.ac.uk.

Received 29 November 2002 ; revised 8 May 2003 ; accepted 29 May 2003

Abstract

Resistance to macrolides in Streptococcus pneumoniae is usually mediated by methylation of 23S ribosomal RNA, encoded by the erm(B) methylation gene, or by efflux mediated by the mef(A) gene. Changes in the L4 and L22 ribosomal proteins have also been associated with macrolide resistance and reduced telithromycin activity. This study generated in vitro mutants from three parent strains of S. pneumoniae: 02J1175 [mef(A) +], 02J1095 [erm(B) +] and NCTC 13593 (macrolide susceptible). The erm(B) and the erm(B) upstream region, the mef(A) genes and the mef(A) upstream and downstream regions, the 23S rRNA genes encoding domains II and V and the L4 and L22 genes of the telithromycin-resistant strains were all amplified by PCR and all, except the mef(A) upstream and downstream regions, were sequenced. No changes were present in any of the genes of the mef(A) + mutants. No changes were found in the erm(B) genes, the 23S rRNA genes or the L4 protein genes of the erm(B) + mutants. However, a Lys-94 to Gln-94 amino acid mutation did occur in a mutant derived from erm(B) + with a telithromycin MIC of >32 mg/L. A 210 base pair deletion in the erm(B) upstream region was also present in this strain. We believe this is the first incidence of a Lys-94 to Gln-94 change in L22 associated with telithromycin resistance and also the first time that such a large deletion in the erm(B) upstream region has been identified in S. pneumoniae.

Keywords: telithromycin, Streptococcus pneumoniae, resistance
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