American Society for Microbiology | Antimicrobial Agents and Chemotherapy (AAC)
As shifts in epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) are the most urgent threats. Although approved beta-lactam-beta-lactamase inhibitor (BL-BLI) combinations address widespread serine beta-lactamases (SBLs) such as CTX-M-15, none provide broad coverage of both clinically important serine- (KPC, OXA-48) and metallo-beta-lactamases (MBLs, e.g. NDM-1). Taniborbactam (formerly VNRX-5133) is a new cyclic boronate BLI in clinical development combined with cefepime for treatment of infections caused by beta-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 prolonged active site residence time (t1/2 of 30-105 min), while in MBLs, it behaves as a competitive inhibitor with Ki 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 E. coli strains overproducing individual enzymes covering classes A, B, C and D, providing up to 1,024-fold shift in MIC. Addition of taniborbactam restored cefepime antibacterial activity in all 102 Enterobacterales and 38/41 P. aeruginosa clinical isolates with MIC90 of 1 and 4 μg/mL representing ≥256- and ≥32-fold improvement in antibacterial activity over cefepime alone. The data demonstrate potent, broad-spectrum rescue of cefepime activity in clinical isolates of CRE and CRPA.
American Chemical Society | Journal of Medicinal Chemistry (JMedChem)
A major resistance mechanism in Gram-negative bacteria is the production of beta-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent beta-lactamases can now confer resistance to other beta-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of beta-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-beta-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided taniborbactam (formerly VNRX-5133), a boronic-acid-containing pan-spectrum beta-lactamase inhibitor. In vitro and in vivo studies demonstrated that taniborbactam restored the activity of beta-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum beta-lactamase inhibitor to enter clinical development.