All tested strains of Streptococcus pyogenes (group A streptococcus, GAS) remain susceptible to penicillin. However, GAS strains
with amino acid substitutions in penicillin-binding proteins that confer decreased
susceptibility to beta-lactam antibiotics have been identified recently. This discovery
raises concerns about emergence of beta-lactam antibiotic resistance in GAS. Whole
genome sequencing recently identified GAS strains with a chimeric penicillin-binding
protein 2X (PBP2X) containing a recombinant segment from Streptococcus dysgalactiae subspecies equisimilis (SDSE). To directly test the hypothesis that the chimeric SDSE-like PBP2X alters
beta-lactam susceptibility in vitro and fitness in vivo, an isogenic mutant strain was generated and virulence assessed in a mouse model
of necrotizing myositis. Compared with naturally occurring and isogenic strains with
a wild-type GAS-like PBP2X, strains with the chimeric SDSE-like PBP2X had reduced
susceptibility in vitro to nine beta-lactam antibiotics. In a mouse model of necrotizing myositis, the strains
had identical fitness in the absence of benzylpenicillin treatment. However, mice
treated intermittently with a subtherapeutic dose of benzylpenicillin had significantly
more colony-forming units recovered from limbs infected with strains with the chimeric
SDSE-like PBP2X. These results show that mutations such as the PBP2X chimera may result
in significantly decreased beta-lactam susceptibility and increased fitness and virulence.
Expanded diagnostic laboratory surveillance, genome sequencing, and molecular pathogenesis
study of potentially emergent beta-lactam antibiotic resistance among GAS are needed.
Graphical abstract
Graphical Abstract
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Article Info
Publication History
Published online: July 14, 2022
Accepted:
June 29,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by NIH grant 1R21AI155842 (J.M.M.) and the Fondren Foundation , Houston Methodist Hospital and Research Institute (J.M.M.).
Disclosures: None.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
