Resistance to the Macrolide Antibiotic Tylosin Is Conferred by Single Methylations at 23S rRNA Nucleotides G748 and A2058 Acting in Synergy

The macrolide antibiotic tylosin has been used extensively in veterinary medicine and exerts potent antimicrobial activity against Gram-positive bacteria. Tylosin-synthesizing strains of the Gram-positive bacterium Streptomyces fradiae protect themselves from their own product by differential expres...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-11, Vol.99 (23), p.14658-14663
Main Authors: Liu, Mingfu, Douthwaite, Stephen
Format: Article
Language:English
Subjects:
Adenine
Antibiotics
Bacteria
Binding Sites
Biochemistry
Biological Sciences
Crystal structure
DNA Primers
Drug Resistance, Bacterial - genetics
Escherichia coli - drug effects
Genes, Bacterial
Guanine
Lincosamides
Macrolides
Methylation
Nucleotides
Plasmids
Ribonucleic acid
RNA
RNA, Ribosomal, 23S - genetics
Streptomyces
Streptomyces - drug effects
Streptomyces - genetics
Sugars
Tylosin - pharmacology
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Summary:The macrolide antibiotic tylosin has been used extensively in veterinary medicine and exerts potent antimicrobial activity against Gram-positive bacteria. Tylosin-synthesizing strains of the Gram-positive bacterium Streptomyces fradiae protect themselves from their own product by differential expression of four resistance determinants, tlrA, tlrB, tlrC, and tlrD. The tlrB and tlrD genes encode methyltransferases that add single methyl groups at 23S rRNA nucleotides G748 and A2058, respectively. Here we show that methylation by neither TlrB nor TlrD is sufficient on its own to give tylosin resistance, and resistance is conferred by the G748 and A2058 methylations acting together in synergy. This synergistic mechanism of resistance is specific for the macrolides tylosin and mycinamycin that possess sugars extending from the 5- and 14-positions of the macrolactone ring and is not observed for macrolides, such as carbomycin, spiramycin, and erythromycin, that have different constellations of sugars. The manner in which the G748 and A2058 methylations coincide with the glycosylation patterns of tylosin and mycinamycin reflects unambiguously how these macrolides fit into their binding site within the bacterial 50S ribosomal subunit.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.232580599