Document Report Card
Basic Information
ID: ALA4699665
Journal: J Med Chem
Title: Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii.
Authors: 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
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 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.
CiteXplore: 33306385