Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5

Journal Article · 17 July 2023 · Nature Communications

DOI: https://doi.org/10.1038/s41467-023-39966-5 · OSTI ID:1989977

Hunashal, Yamanappa; Kumar, Ganesan Senthil ; Choy, Meng S.; D’Andréa, Éverton D.; Da Silva Santiago, Andre ; Schoenle, Marta V.; Desbonnet, Charlene; Arthur, Michel ; Rice, Louis B.; Page, Rebecca; Peti, Wolfgang

Abstract Penicillin-binding proteins (PBPs) are essential for the formation of the bacterial cell wall. They are also the targets of β-lactam antibiotics. In Enterococcus faecium , high levels of resistance to β-lactams are associated with the expression of PBP5, with higher levels of resistance associated with distinct PBP5 variants. To define the molecular mechanism of PBP5-mediated resistance we leveraged biomolecular NMR spectroscopy of PBP5 – due to its size (>70 kDa) a challenging NMR target. Our data show that resistant PBP5 variants show significantly increased dynamics either alone or upon formation of the acyl-enzyme inhibitor complex. Furthermore, these variants also exhibit increased acyl-enzyme hydrolysis. Thus, reducing sidechain bulkiness and expanding surface loops results in increased dynamics that facilitates acyl-enzyme hydrolysis and, via increased β-lactam antibiotic turnover, facilitates β-lactam resistance. Together, these data provide the molecular basis of resistance of clinical E. faecium PBP5 variants, results that are likely applicable to the PBP family.

• Sponsoring Organization: USDOE
• Grant/Contract Number: AC02-76SF00515
• OSTI ID: 1989977
• Journal Information: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723
• Publisher: Nature Publishing GroupCopyright Statement
• Country of Publication: United Kingdom
• Language: English