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

Macrolide overuse and resulting resistance crippled the applicability of one of the most important and successful classes of antibiotics. The rising incidence of invasive infections caused by β‐hemolytic group A and group B streptococci have been paralleled with marked increases in erythromycin and clindamycin resistance. As a result, resistant invasive group A and group B Streptococcus infections have been classified by the CDC as a concerning level threat since 2019. Acquisition of erythromycin resistance methylase ( erm ) genes is a major contributor of the MLS B [macrolide (i.e., erythromycin), lincosamide (i.e., clindamycin), and streptogramin B] resistance phenotype in US isolates. The erm ‐encoded enzymes utilize the methyl‐group from S‐adenosyl‐L‐methionine (SAM) to methylate the adenosine A2058 residue of bacterial ribosomal RNA, which serves as the overlapping rRNA target site for the three MLS B classes of antibiotics. The major mechanism that regulates Erm methyltransferase production is translational attenuation in the 5′ regulatory region upstream of the erm coding sequence. The 5′ regulatory region of erm includes at least one short leader peptide erm L, with the leader peptide ribosome binding site (SD1), non‐translational stem‐loop structures, and the erm start codon with its ribosome binding site (SD2). Binding of a macrolide antibiotic to the ribosome causes stalling during translation of the erm L peptide, which disrupts and alters the formation of inhibitory mRNA hairpins in the erm 5′ regulatory region, thereby releasing the erm SD2‐site from the posterior stem‐loop hairpin, thus allowing Erm protein translation. The streptococcal ErmA, ErmB, and ErmT proteins have conserved structures with primary sequence conservation of residues involved in SAM‐ and rRNA‐binding activity, as well as a high‐level of structural conservation. However, the observed variation in the erm 5′ regulatory region sequences, transcript expression, and ribosome methylation levels associated with these genes and proteins underscore the regulatory complexity of Erm expression. This review aims to present insights into mechanisms of Erm‐mediated resistance, trends in streptococcal epidemiology and treatment, and progress in the development of improved MLS B drugs that effectively block erm ‐mediated resistance.