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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
DOI:
10.1021/acs.jmedchem.0c01535
Authors:
David T.
Davies
(Antabio SAS)
,
Simon
Leiris
(Antabio SAS)
,
Magdalena
Zalacain
(Antabio SAS)
,
Nicolas
Sprynski
(Antabio SAS)
,
Jérôme
Castandet
(Antabio SAS)
,
Justine
Bousquet
(Antabio SAS)
,
Clarisse
Lozano
(Antabio SAS)
,
Agustina
Llanos
(Antabio SAS)
,
Laethitia
Alibaud
(Antabio SAS)
,
Srinivas
Vasa
(GVK Biosciences Pvt. Ltd)
,
Ramesh
Pattipati
(GVK Biosciences Pvt. Ltd)
,
Ravindar
Valige
(GVK Biosciences Pvt. Ltd)
,
Bhaskar
Kummari
(GVK Biosciences Pvt. Ltd)
,
Srinivasu
Pothukanuri
(GVK Biosciences Pvt. Ltd)
,
Cyntia
De Piano
(International Health Management Associates (IHMA))
,
Ian
Morrissey
(International Health Management Associates (IHMA))
,
Kirsty
Holden
(Evotec (UK) Ltd)
,
Peter
Warn
(Evotec (UK) Ltd)
,
Francesca
Marcoccia
(University of Siena)
,
Manuela
Benvenuti
(University of Siena)
,
Cecilia
Pozzi
(University of Siena)
,
Giusy
Tassone
(University of Siena)
,
Stefano
Mangani
(University of Siena)
,
Jean-denis
Docquier
(University of Siena)
,
David
Pallin
(Charles River Laboratories)
,
Richard
Elliot
(Charles River Laboratories)
,
Marc
Lemonnier
(Antabio SAS)
,
Martin
Everett
(Antabio SAS)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
State:
Published (Approved)
Published:
December 2020
Diamond Proposal Number(s):
21741
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.
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I04-Macromolecular Crystallography