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
Davies, David T.; Leiris, Simon; Zalacain, Magdalenaet al.
2020 • In Journal of Medicinal Chemistry, 63 (24), p. 15802–15820
Includes synthesis and characterization of key compounds, experimental procedures for enzyme inhibition assays, in vitro antimicrobial susceptibility testing, efficacy studies, protein crystallization, and collection and processing of diffraction data (with resulting statistics)
[en] 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.
Disciplines :
Life sciences: Multidisciplinary, general & others Microbiology Biochemistry, biophysics & molecular biology Chemistry
Author, co-author :
Davies, David T.
Leiris, Simon
Zalacain, Magdalena
Sprynski, Nicolas
Castandet, Jérôme
Bousquet, Justine
Lozano, Clarisse
Llanos, Agustina
Alibaud, Laethitia
Vasa, Srinivas
Pattipati, Ramesh
Valige, Ravindar
Kummari, Bhaskar
Pothukanuri, Srinivasu
De Piano, Cyntia
Morrissey, Ian
Holden, Kirsty
Warn, Peter
Marcoccia, Francesca
Benvenuti, Manuela
Pozzi, Cecilia
Tassone, Giusy
Mangani, Stefano
Docquier, Jean-Denis ; Université de Liège - ULiège > Département des sciences de la vie > UR InBioS - Centre d'ingénierie des protéines
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
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