1. A Chimeric Penicillin Binding Protein 2X Significantly Decreases in Vitro Beta-Lactam Susceptibility and Increases in Vivo Fitness of Streptococcus pyogenes
- Author
-
Olsen, Randall J, Zhu, Luchang, Mangham, Regan E, Faili, Ahmad, Kayal, Samer, Beres, Stephen B, Musser, Andrew, Jonchère, Laurent, Houston Methodist Hospital [Houston, TX, USA], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], and None
- Subjects
Myositis ,Streptococcus pyogenes ,Recombinant Fusion Proteins ,[SDV]Life Sciences [q-bio] ,Penicillin G ,Penicillins ,beta-Lactams ,Anti-Bacterial Agents ,Pathology and Forensic Medicine ,[SDV] Life Sciences [q-bio] ,Mice ,Streptococcus pneumoniae ,[SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology ,Animals ,Penicillin-Binding Proteins ,Fasciitis, Necrotizing ,[SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology - Abstract
International audience; 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.
- Published
- 2022