Translation-transcription coupled regulation of erm(T) MLSB sub-phenotype expression in the emergent emm92-type group A Streptococcus

In the last decade, invasive group A Streptococcus (iGAS) infections have doubled in the U.S., with equivalent increases in MLS _B (macrolide, lincosamide, and streptogramin B)-resistance. The emm92 -type isolates carrying the erm (T) gene have been associated with an alarming emergence of iGAS infections in people who inject drugs or experiencing homelessness. Our goal was to elucidate the mechanisms behind inducible (iMLS _B ) and constitutive (cMLS _B ) resistance in emm92 isolates. Sequence analysis identified polymorphisms in the erm (T) regulatory region associated with cMLS _B resistance. RT-qPCR and RNAseq revealed increased erm (T) mRNA levels in iMLS _B isolates in response to erythromycin exposure, while cMLS _B 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 iMLS _B isolates cultured with erythromycin and increased clindamycin resistance in cMLS _B isolates were observed.