VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in Enterobacterales and Pseudomonas aeruginosa

Abstract

As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved β-lactam (BL)–β-lactamase inhibitor (BLI) combinations address widespread serine β-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-β-lactamases (KPC, OXA-48) or clinically important metallo-β-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by β-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (Ki) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered Escherichia coli strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102 Enterobacterales clinical isolates tested and 38/41 P. aeruginosa clinical isolates tested with MIC90s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.

Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases

“…Unlike QPX7728, taniborbactam, does not inhibit class D carbapenemases from A. baumannii (27)(28)(29).…”

“…Thus, QPX7728 is a covalent low off-rate inhibitor of serine enzymes. In contrast, inhibition of metallo beta-lactamases by QPX7728 [similar to taniborbactam (27)] proceeds through a simple one-step complex formation typical for "fast on -fast off" inhibitors.…”

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

“…Moreover, several MBL inhibitors, including aspergillomarasmine A (15), dipicolinic acid derivatives (16), ANT431 (17), bisthiazolodines (18) and bismuth antimicrobials (19) have been reported. Recently, VNRX-5133 (taniborbactam), a dual SBL and MBL inhibitor have shown potent activity in combination with cefepime against MBL-producers (20). However, no direct MBL inhibitors are approved for clinical use (21).…”

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.…”