IID572: A New Potentially Best-In-Class β-Lactamase Inhibitor

Abstract

Resistance in Gram-negative bacteria to β-lactam drugs is mediated primarily by the expression of β-lactamases, and co-dosing of β-lactams with a β-lactamase inhibitor (BLI) is a clinically proven strategy to address resistance. New β-lactamases that are not impacted by existing BLIs are spreading and creating the need for development of novel broader spectrum BLIs. IID572 is a novel broad spectrum BLI of the diazabicyclooctane (DBO) class that is able to restore the antibacterial activity of piperacillin against piperacillin/tazobactam-resistant clinical isolates. IID572 is differentiated from other DBOs by its broad inhibition of β-lactamases and the lack of intrinsic antibacterial activity.

Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes

“…First, on November 25, 2020 by guest http://aac.asm.org/ Downloaded from the intrinsic antibacterial activity of DBOs were confirmed, with MICs of 16 µg mL -1 for AVI, 128 µg mL -1 for REL, 2 µg mL -1 for NAC, and ≤ 0.25 µg mL -1 for ZID being observed, both against the wildtype DH5a and the AmpCEC expressing DH5a (Table S5). This is in agreement with reported MIC values with E. coli ATCC 25922 (16 µg mL -1 for AVI, >64 µg mL -1 for REL, 2 µg mL -1 for NAC, and 0.125 µg mL -1 for ZID) (37). The observed antimicrobial activity of DBOs against E.coli has been attributed to different degrees of inhibition of pencillin binding protein 2 ` (20,38).…”

The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections

“…Originally discovered by Novartis, the compound is preclinical evaluation by Boston Pharmaceuticals. BOS-572 does not possess antibacterial activity on its own; thus, it must be combined with a β-lactam partner [171].…”

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

“…IID572 is another type of tricyclic DBO that incorporates a pyrrolidone ring, which replaces the amide functional group, and that was developed by Novartis. 55,56 A late-functionalization strategy was implemented starting from bicyclic acid 6 that was first esterified (Scheme 13). The conjugated double bond was then installed by an α-selenation/oxidation/elimination sequence to give 69 with 21% yield over three steps.…”

“…IID572 did not possess any intrinsic antibiotic effect but exhibited a broad anti-SBL spectrum and could restore susceptibility to piperacillin in some piperacillintazobactam resistant clinical strains. 56…”