Discovery of <b>ANT3310</b>, a Novel Broad-Spectrum Serine β‑Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii

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.