6TPM
Crystal structure of AmpC from E.coli with Relebactam (MK-7655)
Summary for 6TPM
| Entry DOI | 10.2210/pdb6tpm/pdb |
| Descriptor | Beta-lactamase, DI(HYDROXYETHYL)ETHER, (2S,5R)-1-formyl-N-(piperidin-4-yl)-5-[(sulfooxy)amino]piperidine-2-carboxamide, ... (8 entities in total) |
| Functional Keywords | beta lactamase, antibiotic resistance, diazabicyclooctane, dbo, hydrolase |
| Biological source | Escherichia coli (strain K12) |
| Total number of polymer chains | 1 |
| Total formula weight | 40598.07 |
| Authors | Lang, P.A.,Leissing, T.M.,Schofield, C.J.,Brem, J. (deposition date: 2019-12-13, release date: 2020-11-25, Last modification date: 2024-11-13) |
| Primary citation | Lang, P.A.,Leissing, T.M.,Page, M.G.P.,Schofield, C.J.,Brem, J. Structural Investigations of the Inhibition of Escherichia coli AmpC beta-Lactamase by Diazabicyclooctanes. Antimicrob.Agents Chemother., 65:-, 2021 Cited by PubMed Abstract: β-Lactam antibiotics are presently the most important treatments for infections by pathogenic , but their use is increasingly compromised by β-lactamases, including the chromosomally encoded class C AmpC serine-β-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with ceftazidime has stimulated efforts to optimize the DBO core. We report kinetic and structural studies, including four high-resolution crystal structures, concerning inhibition of the AmpC serine-β-lactamase from (AmpC ) by clinically relevant DBO-based inhibitors: avibactam, relebactam, nacubactam, and zidebactam. Kinetic analyses and mass spectrometry-based assays were used to study their mechanisms of AmpC inhibition. The results reveal that, under our assay conditions, zidebactam manifests increased potency (apparent inhibition constant [], 0.69 μM) against AmpC compared to that of the other DBOs ( = 5.0 to 7.4 μM) due to an ∼10-fold accelerated carbamoylation rate. However, zidebactam also has an accelerated off-rate, and with sufficient preincubation time, all the DBOs manifest similar potencies. Crystallographic analyses indicate a greater conformational freedom of the AmpC -zidebactam carbamoyl complex compared to those for the other DBOs. The results suggest the carbamoyl complex lifetime should be a consideration in development of DBO-based SBL inhibitors for the clinically important class C SBLs. PubMed: 33199391DOI: 10.1128/AAC.02073-20 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.72 Å) |
Structure validation
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