6ZXI

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

Summary for 6ZXI

• Entry DOI: 10.2210/pdb6zxi/pdb
• Descriptor: Beta-lactamase, [[(3~{R},6~{R})-6-fluoranyl-1-methanoyl-piperidin-3-yl]amino] hydrogen sulfate, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: beta-lactamase, carbapenemase, ant3310, antibiotic resistance, carbapenem-hydrolyzing beta-lactamase, hydrolase, diazabicyclooctanone inhibitor
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 2
• Total formula weight: 61481.49

Authors

Docquier, J.D.,Pozzi, C.,De Luca, F.,Benvenuti, M.,Mangani, S. (deposition date: 2020-07-29, release date: 2021-08-11, Last modification date: 2024-11-20)

Primary citation

Davies, D.T.,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, J.D.,Pallin, D.,Elliot, R.,Lemonnier, M.,Everett, M.
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.
J.Med.Chem., 63:15802-15820, 2020

PubMed Abstract: The diazabicyclooctanes (DBOs) are a class of serine β-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 β-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 β-lactam antibiotics against carbapenem-resistant (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, , 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.

PubMed: 33306385
DOI: 10.1021/acs.jmedchem.0c01535

Experimental method

X-RAY DIFFRACTION (1.85 Å)