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

Area of Science:

• Microbiology
• Genetics
• Molecular Biology

Background:

• Macrolide resistance in Streptococcus pneumoniae is often mediated by transferable genetic elements like Mega (mef(E)/mel) or erm(B).
• These elements encode efflux pumps, ribosomal protection proteins, or ribosomal methylation, leading to varying resistance levels.
• The global emergence and expansion of strains carrying Mega or erm(B) on mobile genetic elements like Tn2010 pose a significant public health concern.

Purpose of the Study:

• To identify and characterize pneumococcal isolates exhibiting unusually high-level macrolide resistance solely due to the Mega element.
• To investigate the specific genomic insertions of the Mega element associated with this high-level resistance.
• To compare the fitness advantage conferred by different macrolide resistance mechanisms in Streptococcus pneumoniae.

Main Methods:

• Genomic analysis of pneumococcal isolates with high-level macrolide resistance (MICs > 16 μg/ml).
• Identification of specific Mega element genomic insertions (Mega-2.IVa and Mega-2.IVc).
• Deletion studies to confirm the role of mef(E)/mel in macrolide resistance.
• In vitro competition experiments to assess the fitness advantage of resistant strains.

Main Results:

• Identified pneumococcal isolates with high-level macrolide resistance exclusively due to the Mega element [mef(E)/mel], specifically linked to Mega-2.IVa and Mega-2.IVc insertions.
• Confirmed that these isolates lacked erm(B) or known ribosomal mutations, and deletion of mef(E)/mel abolished resistance.
• Demonstrated that high-level macrolide resistance, whether conferred by Mega-2.IVa or erm(B), provides a significant growth fitness advantage in macrolide-containing environments compared to lower-level mef(E)/mel-mediated resistance.

Conclusions:

• Streptococcus pneumoniae can achieve high-level macrolide resistance through macrolide efflux/ribosomal protection mediated by the Mef(E)/Mel system.
• High-level macrolide resistance, irrespective of the specific genetic mechanism (Mega or erm(B)), confers a substantial fitness advantage to S. pneumoniae in the presence of macrolides.
• Understanding these resistance mechanisms and their fitness implications is critical for combating macrolide resistance in pneumococcal infections.