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Antimicrobial Agents and Chemotherapy, February 2008, p. 435-440, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01074-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Telithromycin Resistance in Streptococcus pneumoniae Is Conferred by a Deletion in the Leader Sequence of erm(B) That Increases rRNA Methylation

Respiratory and Meningeal Pathogens Research Unit, National Institute for Communicable Diseases, Medical Research Council and University of the Witwatersrand, Johannesburg, South Africa,¹ GR Micro Ltd., London, United Kingdom,² Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark,³ Hubert Department of Global Health, Rollins School of Public Health, and Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, Georgia⁴

Received 15 August 2007/ Returned for modification 23 October 2007/ Accepted 15 November 2007

A telithromycin-resistant clinical isolate of Streptococcus pneumoniae (strain P1501016) has been found to contain a version of erm(B) that is altered by a 136-bp deletion in the leader sequence. By allele replacement mutagenesis, a second strain of S. pneumoniae (PC13) with a wild-type erm(B) gene was transformed to the telithromycin-resistant phenotype by introduction of the mutant erm(B) gene. Whereas the wild-type PC13 strain showed slight telithromycin resistance only after induction by erythromycin (telithromycin MIC increased from 0.06 to 0.5 µg/ml), the transformed PC13 strain is constitutively resistant (MIC of 16 µg/ml). Expression of erm(B) was quantified by real-time reverse transcription-PCR in the presence of erythromycin or telithromycin; erm(B) expression was significantly higher in the transformed PC13 strain than the wild-type strain. Furthermore, the transformed strain had significantly higher levels of ribosomal methylation in the absence as well as in the presence of the antibiotics. Growth studies showed that the transformed PC13 strain had a shorter lag phase than the wild-type strain in the presence of erythromycin. Telithromycin resistance is conclusively shown to be conferred by the mutant erm(B) gene that is expressed at a constitutively higher level than the inducible wild-type gene. Elevated erm(B) expression results in a higher level of rRNA methylation that presumably hinders telithromycin binding to the ribosome.

Published ahead of print on 3 December 2007.