9d7d | pdb_00009d7d

OXA-58-NA-1-157 20 min complex

spinqualitylabelsall models 9d7d, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9d7d is a 4 chain structure with sequence from Acinetobacter baumannii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: ACT, CO2, Y33 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q2TR58_ACIBA Publication Abstract from PubMed Antibiotic resistance in bacteria is a major global health concern. The wide spread of carbapenemases, bacterial enzymes that degrade the last-resort carbapenem antibiotics, is responsible for multidrug resistance in bacterial pathogens and has further significantly exacerbated this problem. Acinetobacter baumannii is one of the leading nosocomial pathogens due to the acquisition and wide dissemination of carbapenem-hydrolyzing class D beta-lactamases, which have dramatically diminished available therapeutic options. Thus, new antibiotics that are active against multidrug-resistantA. baumannii and carbapenemase inhibitors are urgently needed. Here we report characterization of the interaction of the C5alpha-methyl-substituted carbapenem NA-1-157 with one of the clinically important class D carbapenemases, OXA-58. Antibiotic susceptibility testing shows that the compound is more potent than commercial carbapenems against OXA-58-producingA. baumannii, with a clinically sensitive MIC value of 1 mug/mL. Kinetic studies demonstrate that NA-1-157 is a very poor substrate of the enzyme due mainly to a significantly reduced deacylation rate. Mass spectrometry analysis shows that inhibition of OXA-58 by NA-1-157 proceeds through both the classical acyl-enzyme intermediate and a reversible covalent species. Time-resolved X-ray crystallographic studies reveal that upon acylation of the enzyme, the compound causes progressive decarboxylation of the catalytic lysine residue, thus severely impairing deacylation. Overall, this study demonstrates that the carbapenem NA-1-157 is highly resistant to degradation by the OXA-58 carbapenemase. Decarboxylation of the Catalytic Lysine Residue by the C5alpha-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase.,Toth M, Stewart NK, Maggiolo AO, Quan P, Khan MMK, Buynak JD, Smith CA, Vakulenko SB ACS Infect Dis. 2024 Nov 27. doi: 10.1021/acsinfecdis.4c00671. PMID:39601221 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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