DSpace Collection:https://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/16122026-04-03T04:19:37Z2026-04-03T04:19:37ZMolecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5Hunashal, YamanappaKumar, Ganesan SenthilChoy, Meng S'Andréa, Éverton D DSantiago, Andre Da SilvaSchoenle, Marta VDesbonnet, CharleneArthur, MichelRice, Louis BPage, RebeccaPeti, Wolfganghttps://dspace.nii.res.in//https://dspace.nii.res.in/handle/123456789/15472025-12-05T12:48:54Z2023-01-01T00:00:00ZTitle: Molecular basis of β-lactam antibiotic resistance of ESKAPE bacterium E. faecium Penicillin Binding Protein PBP5
Authors: Hunashal, Yamanappa; Kumar, Ganesan Senthil; Choy, Meng S; 'Andréa, Éverton D D; Santiago, Andre Da Silva; 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.2023-01-01T00:00:00Z