High-Level Macrolide Resistance Due to the Mega Element [ mef (E)/ mel ] in Streptococcus pneumoniae

Transferable genetic elements conferring macrolide resistance in can encode the efflux pump and ribosomal protection protein, (E)/ , in an operon of the macrolide efflux genetic assembly (Mega) element- or induce ribosomal methylation through a methyltransferase encoded by (B). During the past 30 years, strains that contain Mega or (B) or both elements on Tn and other Tn -like composite mobile genetic elements have emerged and expanded globally. In this study, we identify and define pneumococcal isolates with unusually high-level macrolide resistance (MICs > 16 μg/ml) due to the presence of the Mega element [ (E)/ ] alone. High-level resistance due to (E)/ was associated with at least two specific genomic insertions of the Mega element, designated Mega-2.IVa and Mega-2.IVc. Genome analyses revealed that these strains do not possess (B) or known ribosomal mutations. Deletion of (E)/ in these isolates eliminated macrolide resistance. We also found that Mef(E) and Mel of Tn -containing pneumococci were functional but the high-level of macrolide resistance was due to Erm(B). Using competition experiments in the presence of macrolides, high-level macrolide-resistant conferred by either Mega-2.IVa or (B), had a growth fitness advantage over the lower-level, (E)/ -mediated macrolide-resistant phenotypes. These data indicate the ability of to generate high-level macrolide resistance by macrolide efflux/ribosomal protection [Mef(E)/Mel] and that high-level resistance regardless of mechanism provides a fitness advantage in the presence of macrolides.