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

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.

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

“…The syntheses of various DBOs have been recently reported by Davies and colleagues, starting from the commercially available 5-benzyloxyamino-piperidine-2-carboxylic acid ethyl ester—oxalate salt [ 127 ]. With the same procedure, it is also possible to start using the compound 4 obtained during the synthesis of avibactam, as reported in the Scheme 16 .…”

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

“…ANT3310: ANT3310 is the derivative of avibactam in which the carboxamide group of avibactam has been replaced with fluorine atoms (Scheme 4). This compound has been useful in restoring the carbapenem activity against OXA as well as other SBL-carrying carbapenem-resistant Acinetobacter baumannii strains in in vivo mouse infection models [68]. Thio-substituted DBOs: Researchers from Shiniogi pharmaceuticals reported a series of thio-substituted DBO derivatives in which the C2 position of DBO was transformed into sulfide, which was then oxidized to sulfinates and sulfones.…”

“…HCl) [69,70] ANT3310: ANT3310 is the derivative of avibactam in which the carboxamide group of avibactam has been replaced with fluorine atoms (Scheme 4). This compound has been useful in restoring the carbapenem activity against OXA-CRAB as well as other SBLcarrying carbapenem-resistant Acinetobacter baumannii strains in in vivo mouse infection models [68].…”

Azetidinimines as a novel series of non-covalent broad-spectrum inhibitors of β-lactamases with submicromolar activities against carbapenemases KPC-2 (class A), NDM-1 (class B) and OXA-48 (class D)

“…Since 2012 several new broad-spectrum inhibitors of class A and class C β-lactamases have emerged. Of significant interest, avibactam [9,10] and vaborbactam [11] (Figure 1b) were approved by the FDA for clinical use whilst many of their congeners, in particular diazabicyclooctanes, [12][13][14][15][16][17][18][19][20] and various boron derivatives (see below), including benzosiloxaboroles, [21] are currently undergoing preclinical or clinical development. These compounds are mainly able to efficiently inhibit SBLs, including carbapenemases, of class A, C and sometimes D, but generally do not inhibit MBLs (class B).…”