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

AUTOR(ES)

Pfister, Peter

FONTE

National Academy of Sciences

RESUMO

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 23S 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.

Documentos Relacionados

• Mutation at the position 2058 of the 23S rRNA as a cause of macrolide resistance in Streptococcus pyogenes
• Macrolide Resistance Conferred by Base Substitutions in 23S rRNA
• Mutation in 23S rRNA Associated with Macrolide Resistance in Neisseria gonorrhoeae
• Detection and Quantification of Macrolide Resistance Mutations at Positions 2058 and 2059 of the 23S rRNA Gene by Pyrosequencing
• Resistance to the macrolide antibiotic tylosin is conferred by single methylations at 23S rRNA nucleotides G748 and A2058 acting in synergy