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
posted on 2020-12-11, 19:42authored byDavid T. Davies, Simon Leiris, Magdalena Zalacain, Nicolas Sprynski, Jérôme Castandet, Justine Bousquet, Clarisse Lozano, Agustina Llanos, Laethitia Alibaud, Srinivas Vasa, Ramesh Pattipati, Ravindar Valige, Bhaskar Kummari, Srinivasu Pothukanuri, Cyntia De Piano, Ian Morrissey, Kirsty Holden, Peter Warn, Francesca Marcoccia, Manuela Benvenuti, Cecilia Pozzi, Giusy Tassone, Stefano Mangani, Jean-Denis Docquier, David Pallin, Richard Elliot, Marc Lemonnier, Martin Everett
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.