| Autor: |
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 |
| Předmět: |
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| Zdroj: |
Nature Communications; 7/17/2023, Vol. 14 Issue 1, p1-12, 12p |
| Abstrakt: |
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. Penicillin Binding Proteins (PBPs) are the main targets of β-lactam antibiotics. Here the authors use NMR spectroscopy, crystallography and microbiology to define the dynamics of E. faecium PBP5 in solution and show that increased acyl-enzyme hydrolysis correlates with increased resistance. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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