Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 for MRSA β-lactam resistance.
Mélanie Roch, Emmanuelle Lelong, Olesya O Panasenko, Roberto Sierra, Adriana Renzoni, William L Kelley
Author Information
Mélanie Roch: 1Department of Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, 1 rue Michel-Servet, Geneva, CH-1211 Switzerland.
Emmanuelle Lelong: 2Service of Infectious Diseases and Department of Medical Specialties, University Hospital and Medical School of Geneva, 4 rue Gabrielle-Perret-Gentil, Geneva, CH-1206 Switzerland.
Olesya O Panasenko: 1Department of Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, 1 rue Michel-Servet, Geneva, CH-1211 Switzerland.
Roberto Sierra: 1Department of Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, 1 rue Michel-Servet, Geneva, CH-1211 Switzerland.
Adriana Renzoni: 2Service of Infectious Diseases and Department of Medical Specialties, University Hospital and Medical School of Geneva, 4 rue Gabrielle-Perret-Gentil, Geneva, CH-1206 Switzerland.
William L Kelley: 1Department of Microbiology and Molecular Medicine, University Hospital and Medical School of Geneva, 1 rue Michel-Servet, Geneva, CH-1211 Switzerland. ORCID
is a major human pathogen and represents a clinical challenge because of widespread antibiotic resistance. Methicillin resistant (MRSA) is particularly problematic and originates by the horizontal acquisition of encoding PBP2a, an extracellular membrane anchored transpeptidase, which confers resistance to β-lactam antibiotics by allosteric gating of its active site channel. Herein, we show that dual disruption of PrsA, a lipoprotein chaperone displaying anti-aggregation activity, together with HtrA1, a membrane anchored chaperone/serine protease, resulted in severe and synergistic attenuation of PBP2a folding that restores sensitivity to β-lactams such as oxacillin. Purified PBP2a has a pronounced unfolding transition initiating at physiological temperatures that leads to irreversible precipitation and complete loss of activity. The concordance of genetic and biochemical data highlights the necessity for extracellular protein folding factors governing MRSA β-lactam resistance. Targeting the PBP2a folding pathway represents a particularly attractive adjuvant strategy to combat antibiotic resistance.
