23S rRNA base pair 2057-2611 determines ketolide susceptibility and fitness cost of the macrolide resistance mutation 2058A→G

Peter Pfister, Natascia Corti, Sven Hobbie, Christian Bruell, Raz Zarivach, Ada Yonath, Erik C. Böttger

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

The 23S rRNA A2058G alteration mediates macrolide, lincosamide, and streptogramin B resistance in the bacterial domain and determines the selectivity of macrolide antibiotics for eubacterial ribosomes, as opposed to eukaryotic ribosomes. However, this mutation is associated with a disparate resistance phenotype: It confers high-level resistance to ketolides in mycobacteria but only marginally affects ketolide susceptibility in streptococci. We used site-directed mutagenesis of nucleotides within domain V of 23S rRNA to study the molecular basis for this disparity. We show that mutational alteration of the polymorphic 2057-2611 base pair from A-U to G-C in isogenic mutants of Mycobacterium smegmatis significantly affects susceptibility to ketolides but does not influence susceptibility to other macrolide antibiotics. In addition, we provide evidence that the 2057-2611 polymorphism determines the fitness cost of the 235 rRNA A2058G resistance mutation. Supported by structural analysis, our results indicate that polymorphic nucleotides mediate the disparate phenotype of genotypically identical resistance mutations and provide an explanation for the large species differences in the epidemiology of defined drug resistance mutations.

Original languageEnglish
Pages (from-to)5180-5185
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number14
DOIs
StatePublished - 5 Apr 2005
Externally publishedYes

Keywords

  • Antibiotics
  • Conformation
  • Ketolides
  • Ribosomes
  • Structure

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