6zxi

Crystal Structure of the OXA-48 Carbapenem-Hydrolyzing Class D beta-Lactamase in Complex with the DBO inhibitor ANT3310Crystal Structure of the OXA-48 Carbapenem-Hydrolyzing Class D beta-Lactamase in Complex with the DBO inhibitor ANT3310

Structural highlights 6zxi is a 2 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: , , , Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q6XEC0_KLEPN Publication Abstract from PubMed The diazabicyclooctanes (DBOs) are a class of serine beta-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of beta-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of beta-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO "critical priority pathogen" producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure-activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens. Discovery of ANT3310, a Novel Broad-Spectrum Serine beta-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii.,Davies DT, Leiris S, Zalacain M, Sprynski N, Castandet J, Bousquet J, Lozano C, Llanos A, Alibaud L, Vasa S, Pattipati R, Valige R, Kummari B, Pothukanuri S, De Piano C, Morrissey I, Holden K, Warn P, Marcoccia F, Benvenuti M, Pozzi C, Tassone G, Mangani S, Docquier JD, Pallin D, Elliot R, Lemonnier M, Everett M J Med Chem. 2020 Dec 24;63(24):15802-15820. doi: 10.1021/acs.jmedchem.0c01535. , Epub 2020 Dec 11. PMID:33306385 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 6zxi, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image