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Antimicrobial Agents and Chemotherapy, June 2002, p. 1629-1633, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1629-1633.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Activity of the Ketolide Telithromycin Is Refractory to Erm Monomethylation of Bacterial rRNA

Mingfu Liu and Stephen Douthwaite*

Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark

Received 18 July 2001/ Returned for modification 18 November 2001/ Accepted 7 February 2002

Methylation of specific nucleotides in rRNA is one of the means by which bacteria achieve resistance to macrolides-lincosamides-streptogramin B (MLSB) and ketolide antibiotics. The degree of resistance is determined by how effectively the rRNA is methylated. We have implemented a bacterial system in which the rRNA methylations are defined, and in this study we investigate what effect Erm mono- and dimethylation of the rRNA has on the activity of representative MLSB and ketolide antibiotics. In the test system, >80% of the rRNA molecules are monomethylated by ErmN (TlrD) or dimethylated by ErmE. ErmE dimethylation confers high resistance to all the MLSB and ketolide drugs. ErmN monomethylation predictably confers high resistance to the lincosamides clindamycin and lincomycin, intermediate resistance to the macrolides clarithromycin and erythromycin, and low resistance to the streptogramin B pristinamycin IA. In contrast to the macrolides, monomethylation only mildly affects the antimicrobial activities of the ketolides HMR 3647 (telithromycin) and HMR 3004, and these drugs remain 16 to 250 times as potent as clarithromycin and erythromycin. These differences in the macrolide and ketolide activities could explain the recent reports of variation in the MICs of telithromycin for streptococcal strains that have constitutive erm MLSB resistance and are highly resistant to erythromycin.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark. Phone: (45) 65 50 23 95. Fax: (45) 65 50 24 67. E-mail: srd{at}bmb.sdu.dk.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1629-1633, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1629-1633.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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