The tylosin-resistance methyltransferase RlmA(II) (TlrB) modifies the N-1 position of 23S rRNA nucleotide G748

J Mol Biol. 2004 Apr 9;337(5):1073-7. doi: 10.1016/j.jmb.2004.02.030.

Abstract

The methyltransferase RlmA(II) (TlrB) confers resistance to the macrolide antibiotic tylosin in the drug-producing strain Streptomyces fradiae. The resistance conferred by RlmA(II) is highly specific for tylosin, and no resistance is conferred to other macrolide drugs, or to lincosamide and streptogramin B (MLS(B)) drugs that bind to the same region on the bacterial ribosome. In this study, the methylation site of RlmA(II) is identified unambiguously by liquid chromatography/electrospray ionization mass spectrometry as the N-1 position of 23S rRNA nucleotide G748. This position is contacted by the mycinose sugar moiety of tylosin, which is absent from the other drugs. The selective resistance to tylosin conferred by m(1)G748 illustrates how differences in drug structure facilitate the drug fit at the MLS(B)-binding site. This observation is of relevance for the rational design of novel antimicrobials targeting the MLS(B) site, especially if the antimicrobials are to be used against pathogens possessing m(1)G748.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Drug Resistance, Microbial*
  • Methylation
  • Methyltransferases / metabolism*
  • RNA, Ribosomal, 23S / metabolism*
  • Spectrometry, Mass, Electrospray Ionization
  • Streptomyces / enzymology
  • Structure-Activity Relationship
  • Tylosin / chemistry
  • Tylosin / pharmacology*

Substances

  • RNA, Ribosomal, 23S
  • Methyltransferases
  • TlrB protein, Streptomyces fradiae
  • Tylosin