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

Yamanappa Hunashal, Ganesan Senthil Kumar, Meng S. Choy, Éverton D. D’Andréa, Andre Silva Santiago, Marta V. Schoenle, Charlene Desbonnet, Michel Arthur, Louis B. Rice, Rebecca Page and Wolfgang Peti ()
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Yamanappa Hunashal: University of Connecticut Health Center
Ganesan Senthil Kumar: University of Connecticut Health Center
Meng S. Choy: University of Connecticut Health Center
Éverton D. D’Andréa: University of Arizona
Andre Silva Santiago: University of Connecticut Health Center
Marta V. Schoenle: University of Arizona
Charlene Desbonnet: Warren Alpert Medical School of Brown University
Michel Arthur: Université Paris Cité
Louis B. Rice: Warren Alpert Medical School of Brown University
Rebecca Page: University of Connecticut Health Center
Wolfgang Peti: University of Connecticut Health Center

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39966-5

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