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Antimicrobial Agents and Chemotherapy, January 2004, p. 143-150, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.143-150.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Basis of Intrinsic Macrolide Resistance in the Mycobacterium tuberculosis Complex

Karolína Buriánková,1,2,{dagger} Florence Doucet-Populaire,3,4,{dagger} Olivier Dorson,4 Anne Gondran,1,{ddagger} Jean-Claude Ghnassia,4 Jaroslav Weiser,2 and Jean-Luc Pernodet1*

Institut de Génétique et Microbiologie, UMR CNRS 8621, Université Paris-Sud 11, 91405 Orsay,1 UFR des Sciences Pharmaceutiques et Biologiques, Université Paris 5, 75006 Paris,3 Hôpital de Versailles, 78157 Le Chesnay France,4 Institute of Microbiology, Academy of Sciences of the Czech Republic, 14220 Prague, Czech Republic2

Received 7 July 2003/ Returned for modification 28 July 2003/ Accepted 8 October 2003

The intrinsic resistance of the Mycobacterium tuberculosis complex (MTC) to most antibiotics, including macrolides, is generally attributed to the low permeability of the mycobacterial cell wall. However, nontuberculous mycobacteria (NTM) are much more sensitive to macrolides than members of the MTC. A search for macrolide resistance determinants within the genome of M. tuberculosis revealed the presence of a sequence encoding a putative rRNA methyltransferase. The deduced protein is similar to Erm methyltransferases, which confer macrolide-lincosamide-streptogramin (MLS) resistance by methylation of 23S rRNA, and was named ErmMT. The corresponding gene, ermMT (erm37), is present in all members of the MTC but is absent in NTM species. Part of ermMT is deleted in some vaccine strains of Mycobacterium bovis BCG, such as the Pasteur strain, which lack the RD2 region. The Pasteur strain was susceptible to MLS antibiotics, whereas MTC species harboring the RD2 region were resistant to them. The expression of ermMT in the macrolide-sensitive Mycobacterium smegmatis and BCG Pasteur conferred MLS resistance. The resistance patterns and ribosomal affinity for erythromycin of Mycobacterium host strains expressing ermMT, srmA (monomethyltransferase from Streptomyces ambofaciens), and ermE (dimethyltransferase from Saccharopolyspora erythraea) were compared, and the ones conferred by ErmMT were similar to those conferred by SrmA, corresponding to the MLS type I phenotype. These results suggest that ermMT plays a major role in the intrinsic macrolide resistance of members of the MTC and could be the first example of a gene conferring resistance by target modification in mycobacteria.

* Corresponding author. Mailing address: Institut de Génétique et Microbiologie, UMR CNRS 8621, Université Paris-Sud 11, BÂtiment 400, 91405 Orsay Cedex, France. Phone: (33) 1 69154641. Fax: (33) 1 69154544. E-mail: jean-luc.pernodet{at}igmors.u-psud.fr.

{dagger} The two first authors contributed equally to this work.

{ddagger} Present address: Aventis Pharma SA, Process Development Biochemistry, 94403 Vitry-sur-Seine Cedex, France.

Antimicrobial Agents and Chemotherapy, January 2004, p. 143-150, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.143-150.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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