Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections

Abstract

A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant “superbugs” has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.

Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae , Pseudomonas aeruginosa, and Acinetobacter baumannii

“…Taniborbactam and QPX7728 inhibit NDM and VIM metallo beta-lactamases with a similar potency, but taniborbactam lacks inhibitory activity of OXA carbapenemases from Acinetobacter (4,5).…”

“…PVmax, minimal potentiating concentration of the BLI to reduce meropenem MIC to the level seen in the parent strain that lacks KPC, which corresponds to complete inhibition of KPC 3. QPX, QPX7728 and VAB, vaborbactam at 4 µg/ml4 Duplication of two amino acids, Gly134 and Asp135, located within the L3 internal loop and associated with the reduced susceptibility to carbapenems due to constriction of the channel ompK35_fs and ompK36_fs, truncated porins due to the frame-shift mutation; ramR*, truncated ramR due to the stop codon; FL, full length; NF, non-functional; BL, basal level; Up, overexpressed; down, downregulated.on September 8, 2020 by guest http://aac.asm.org/ Downloaded from…”

Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance

“…Indeed, many research groups have developed MBL inhibitors and confirmed their activity against purified MBL enzymes in vitro; however, most inhibitors showed extremely low activity toward live MBL-producing bacteria, suggesting that their permeativity of the bacterial outer membrane is low (7). Thus, only a few MBL inhibitors, such as ME1071, developed by Meiji Seika Pharma (8), and cyclic boronates (9,10), including VNRX-5133 (taniborbactam), developed by Venatorx (11)(12)(13), and ANT431, developed by Antabio SAS (14), are reportedly active against MBL-producing clinical isolates. Nonetheless, none of these compounds have been approved for clinical use.…”

Critical analysis of antibacterial agents in clinical development

“…Taniborbactam is a bicyclic boronate and acts as a dual action inhibitor of both serine β lactamases (SBLs) and MBLs 47,48 . The broad inhibitory activity includes class A and class C enzymes as well as the MBLs NDM and VIM, but not IMP, and moderately the OXA48 carbapenemase (class D) 47 .…”