Background:
To date, all tested strains of Streptococcus pyogenes (group A streptococcus, GAS) are susceptible to penicillin. However, GAS strains with mutations altering the amino acid sequence of penicillin binding proteins and conferring decreased susceptibility to beta-lactam antibiotics have been identified recently. Together, these discoveries raise concerns about possible emergence of beta-lactam antibiotic resistance in GAS.
Methods:
Whole genome sequencing of GAS isolates recovered in Rennes, France identified strains with a chimeric penicillin binding protein 2X (PBP2X) containing part of a Streptococcus dysgalactiae subspecies equisimilis (SDSE) PBP2X. Compared to genetically closely related strains with a GAS-like PBP2X, strains with the chimeric PBP2X had decreased susceptibility to beta-lactam antibiotics. To test the hypothesis that the chimeric PBP2X altered beta-lactam susceptibility in vitro and fitness in vivo, we generated an isogenic mutant strain and tested fitness in a mouse model of necrotizing myositis.
Results:
Compared to the isogenic GAS-like strain, the SDSE-like strain had reduced susceptibility in vitro to eight beta-lactam antibiotics. In a mouse model of necrotizing myositis, the SDSE-like and GAS-like strains had identical fitness in the absence of penicillin treatment. However, in the presence of intermittent subtherapeutic penicillin treatment, significantly more CFUs were recovered from mouse limbs infected with the SDSE-like strain than the GAS-like strain. Histopathology examination showed the SDSE-like strain caused larger lesions with more tissue destruction.
Conclusions:
Mutations, such as the PBP2x chimera, may result in GAS strains with decreased antibiotic susceptibility in vitro and increased fitness in vivo. Enhanced surveillance and molecular study of potentially emergent beta-lactam antibiotic resistance among GAS is warranted.