| Autor: |
Yamanappa Hunashal, Ganesan Senthil Kumar, Meng S. Choy, Éverton D. D’Andréa, Andre Da Silva Santiago, Marta V. Schoenle, Charlene Desbonnet, Michel Arthur, Louis B. Rice, Rebecca Page, Wolfgang Peti |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-12 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-39966-5 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Full text from SpringerLink