Integrative Reverse Genetic Analysis Identifies Polymorphisms Contributing to Decreased Antimicrobial Agent Susceptibility in Streptococcus pyogenes

Abstract

The recent demonstration that naturally occurring amino acid substitutions in Streptococcus pyogenes PBP2X are sufficient to cause severalfold reduced susceptibility to multiple β-lactam antibiotics in vitro raises the concern that these therapeutic agents may become compromised. Substitutions in PBP2X are common first-step mutations that, with the incremental accumulation of additional adaptive mutations within the PBPs, can result in high-level resistance.

Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired reduced folate transporter

“…TB08 and NS5347 both belong to emmST 4.2 and MLST 289 yet differ in their carriage of thfT). Our results are supported by a recent study 28 , and suggest horizontal gene transfer of thfT between related Streptococcus species is the primary method of acquisition of this element. Intriguingly, the thfT locus is also adjacent to a horizontally-acquired penicillin-binding protein (pbp2b) 28 .…”

“…equisimilis and S. dysgalactiae subsp. dysgalactiae strains 28 , suggesting a likely common origin. Examination of publicly available S. dysgalactiae genome sequences from refseq revealed that carriage of thfT was also uncommon in this species (3/136 strains; Supplementary Table 9), with no strains identified as carrying both thfT and a TMP resistance gene.…”

Host-dependent resistance of Group A Streptococcus to sulfamethoxazole mediated by a horizontally-acquired ECF transporter S component

“…equisimilis, suggesting a likely common origin. These results are further supported by a recent study 16 , and suggest horizontal gene transfer of thfT between these species is the primary method of acquisition of this element.…”

“…equisimilis and S. dysgalactiae subsp. dysgalactiae 16 . These results suggest that thfT could be a novel AMR gene that is up-regulated in TB08-2-14 due to a mutation in the thfT promoter region.…”

Editorial: Streptococci in infectious diseases – pathogenic mechanisms and host immune responses

“…Of concern, two isolates showed reduced susceptibility to ceftriaxone and were found to have unique alleles at pbp2X and pbp1A . Several studies identified point mutations within pbp2x , which were associated with reduced or non-susceptibility to β-lactam antibiotics in streptococci (Southon et al, 2020 ; Mcgee et al, 2021 ; Beres et al, 2022 ). Therefore, emergence of such clones warrants ongoing monitoring.…”