5FGZ
E. coli PBP1b in complex with FPI-1465
Summary for 5FGZ
| Entry DOI | 10.2210/pdb5fgz/pdb |
| Descriptor | Penicillin-binding protein 1B, MOENOMYCIN, [[(3~{R},6~{S})-1-methanoyl-6-[[(3~{S})-pyrrolidin-3-yl]oxycarbamoyl]piperidin-3-yl]amino] hydrogen sulfate, ... (4 entities in total) |
| Functional Keywords | penicillin-binding-protein, inhibitor, complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Escherichia coli (strain K12) |
| Total number of polymer chains | 1 |
| Total formula weight | 85213.28 |
| Authors | King, D.T.,Strynadka, N.C.J. (deposition date: 2015-12-21, release date: 2016-01-20, Last modification date: 2024-10-09) |
| Primary citation | King, A.M.,King, D.T.,French, S.,Brouillette, E.,Asli, A.,Alexander, J.A.,Vuckovic, M.,Maiti, S.N.,Parr, T.R.,Brown, E.D.,Malouin, F.,Strynadka, N.C.,Wright, G.D. Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-beta-Lactamases and Penicillin-Binding Proteins. Acs Chem.Biol., 11:864-868, 2016 Cited by PubMed Abstract: Avibactam is a diazabicyclooctane β-lactamase inhibitor possessing outstanding but incomplete efficacy against multidrug-resistant Gram-negative pathogens in combination with β-lactam antibiotics. Significant pharmaceutical investment in generating derivatives of avibactam warrants a thorough characterization of their activity. We show here through structural and kinetic analysis that select diazabicyclooctane derivatives display effective but varied inhibition of two clinically important β-lactamases (CTX-M-15 and OXA-48). Furthermore, these derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 μg/mL) against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp. Imaging of cell phenotype along with structural and biochemical experiments unambiguously demonstrate that this activity, in E. coli, is a result of targeting penicillin-binding protein 2. Our results suggest that structure-activity relationship studies for the purpose of drug discovery must consider both β-lactamases and penicillin-binding proteins as targets. We believe that this approach will yield next-generation combination or monotherapies with an expanded spectrum of activity against currently untreatable Gram-negative pathogens. PubMed: 26731698DOI: 10.1021/acschembio.5b00944 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.85 Å) |
Structure validation
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