The Complexity of erm-Mediated Resistance: Structural and Functional Perspectives From β-Hemolytic Streptococci

Area of Science:

• Microbiology and Infectious Diseases
• Molecular Biology
• Pharmacology

Background:

• Overuse of macrolide antibiotics has led to widespread resistance, diminishing the effectiveness of this critical drug class.
• Invasive infections caused by β-hemolytic group A and B streptococci are rising, with increasing resistance to erythromycin and clindamycin.
• The Centers for Disease Control and Prevention (CDC) has classified resistant invasive streptococcal infections as a concerning threat since 2019.

Purpose of the Study:

• To review the mechanisms of Erm-mediated macrolide, lincosamide, and streptogramin B (MLS_B) resistance in streptococci.
• To examine epidemiological trends and treatment challenges associated with resistant streptococcal infections.
• To highlight progress in developing novel MLS_B drugs that overcome erm-mediated resistance.

Main Methods:

• Analysis of the molecular mechanisms of translational attenuation regulating Erm methyltransferase production.
• Review of conserved structural and sequence features of streptococcal ErmA, ErmB, and ErmT proteins.
• Examination of variations in erm 5' regulatory regions, transcript expression, and ribosome methylation levels.

Main Results:

• Erythromycin resistance methylase (erm) genes are a primary driver of the MLS_B resistance phenotype in US streptococcal isolates.
• Erm-encoded enzymes methylate bacterial ribosomal RNA at the A2058 adenosine residue, the shared target site for MLS_B antibiotics.
• Macrolide binding to ribosomes stalls translation of the leader peptide, altering mRNA hairpin formation and enabling Erm protein synthesis.

Conclusions:

• Erm-mediated resistance presents a significant challenge to treating streptococcal infections, necessitating a deeper understanding of regulatory complexity.
• Conserved structural elements in Erm proteins suggest a common mechanism of action, despite variations in regulatory regions.
• Developing new MLS_B drugs that circumvent Erm-mediated resistance is essential for effective clinical management of invasive streptococcal diseases.