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A Chimeric Penicillin Binding Protein 2X Significantly Decreases in Vitro Beta-Lactam Susceptibility and Increases in Vivo Fitness of Streptococcus pyogenes

  • Randall J. Olsen
    Correspondence
    Address correspondence to Randall J. Olsen, M.D., Ph.D., Houston Methodist Research Institute, 6565 Fannin St., Ste B490, Houston, TX 77030.
    Affiliations
    Laboratory of Molecular and Translational Human Infectious Disease Research, Center for Infectious Diseases, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas

    Departments of Pathology and Laboratory Medicine and Microbiology and Immunology, Weill Cornell Medical College, New York, New York
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  • Luchang Zhu
    Affiliations
    Laboratory of Molecular and Translational Human Infectious Disease Research, Center for Infectious Diseases, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas

    Departments of Pathology and Laboratory Medicine and Microbiology and Immunology, Weill Cornell Medical College, New York, New York
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  • Regan E. Mangham
    Affiliations
    Laboratory of Molecular and Translational Human Infectious Disease Research, Center for Infectious Diseases, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas
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  • Ahmad Faili
    Affiliations
    Inserm, CIC 1414, Rennes, France

    Faculté de Pharmacie, Université Rennes 1, Rennes, France

    CHU de Rennes, Service de Bacteriologie-Hygiène Hospitalière, Rennes, France
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  • Samer Kayal
    Affiliations
    Inserm, CIC 1414, Rennes, France

    CHU de Rennes, Service de Bacteriologie-Hygiène Hospitalière, Rennes, France

    Faculté de Médecine, Université Rennes 1, Rennes, France
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  • Stephen B. Beres
    Affiliations
    Laboratory of Molecular and Translational Human Infectious Disease Research, Center for Infectious Diseases, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas
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  • James M. Musser
    Affiliations
    Laboratory of Molecular and Translational Human Infectious Disease Research, Center for Infectious Diseases, Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Houston Methodist Hospital, Houston, Texas

    Departments of Pathology and Laboratory Medicine and Microbiology and Immunology, Weill Cornell Medical College, New York, New York
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      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.

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