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J. Biol. Chem., Vol. 280, Issue 47, 38942-38947, November 25, 2005

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Methyltransferase Erm(37) Slips on rRNA to Confer Atypical Resistance in Mycobacterium tuberculosis^*

Christian Toft Madsen1, Lene Jakobsen, Karolina Buriánková2, Florence Doucet-Populaire¶, Jean-Luc Pernodet, and Stephen Douthwaite3

From the Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark, Institut de Génétique et Microbiologique, UMR CNRS 8621, Université Paris-Sud 11, 91405 Orsay, France, and ^¶Microbiologie, UFR des Sciences Pharmaceutiques et Biologiques, Université Paris 5, 75006 Paris, France

Members of the Mycobacterium tuberculosis complex possess a resistance determinant, erm(37) (also termed ermMT), which is a truncated homologue of the erm genes found in a diverse range of drug-producing and pathogenic bacteria. All erm genes examined thus far encode N⁶-monomethyltransferases or N⁶,N⁶-dimethyltransferases that show absolute specificity for nucleotide A2058 in 23 S rRNA. Monomethylation at A2058 confers resistance to a subset of the macrolide, lincosamide, and streptogramin B (MLS_B) group of antibiotics and no resistance to the latest macrolide derivatives, the ketolides. Dimethylation at A2058 confers high resistance to all MLS_B and ketolide drugs. The erm(37) phenotype fits into neither category. We show here by tandem mass spectrometry that Erm(37) initially adds a single methyl group to its primary target at A2058 but then proceeds to attach additional methyl groups to the neighboring nucleotides A2057 and A2059. Other methyltransferases, Erm(E) and Erm(O), maintain their specificity for A2058 on mycobacterial rRNA. Erm(E) and Erm(O) have a full-length C-terminal domain, which appears to be important for stabilizing the methyltransferases at their rRNA target, and this domain is truncated in Erm(37). The lax interaction of the M. tuberculosis Erm(37) with its rRNA produces a unique methylation pattern and confers resistance to the ketolide telithromycin.

Received for publication, May 25, 2005 , and in revised form, September 15, 2005.

^* This work was supported by the Danish Research Agency (FNU-rammebevilling 21-04-0520) and the Nucleic Acid Center of the Danish Grundforskningsfond. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Danish Institute of Agricultural Sciences, DK-1871 Frederiksberg C, Denmark.

² Present address: Institute of Microbiology, Academy of Sciences, 14220 Prague, Czech Republic.

³ To whom correspondence should be addressed. Tel.: 45-6550-2395; Fax: 45-6550-2467; E-mail: srd{at}bmb.sdu.dk.

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