Regulation of erm(T) MLSB phenotype expression in the emergent emm92 type group A Streptococcus

In the last decade, invasive group A Streptococcus (iGAS) infections have doubled in the US, with equivalent increases in MLSB(macrolide,lincosamide,andstreptograminB)-resistance.Theemm92 type isolates carrying the erm(T) gene have been associated with an alarming emergence of iGAS infections in people who inject drugs or experience homelessness. Our goal was to elucidate the mechanisms behind inducible (iMLSB) and constitutive (cMLSB) resistance in emm92 isolates. Sequence analysis identified polymorphisms in the erm(T) regulatory region associated with cMLSB resistance. RT-qPCR and RNAseq revealed increased erm(T) mRNA levels in iMLSB isolates in response to erythromycin exposure, while cMLSB isolates exhibited high erm(T) expression independent from antibiotic exposure. Transcription results were coupled with shifting levels of ribosomal methylation. A homology model of the ErmT enzyme identified structural elements and residues conserved in methyltransferases. Delayed growth of iMLSB isolates cultured with erythromycin and increased clindamycin resistance in cMLSB isolates were observed.