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VNRX-5133 (Taniborbactam), a broad-spectrum inhibitor of serine- and metallo-β-lactamases, restores activity of cefepime in Enterobacterales and Pseudomonas aeruginosa

DOI: 10.1128/AAC.01963-19 DOI Help

Authors: Jodie C. Hamrick (Venatorx Pharmaceuticals Incorporated) , Jean-Denis Docquier (University of Siena) , Tsuyoshi Uehara (Venatorx Pharmaceuticals Incorporated) , Cullen L. Myers (Venatorx Pharmaceuticals Incorporated) , David A. Six (Venatorx Pharmaceuticals Incorporated) , Cassandra L. Chatwin (Venatorx Pharmaceuticals Incorporated) , Kaitlyn J. John (Venatorx Pharmaceuticals Incorporated) , Salvador F. Vernacchio (Venatorx Pharmaceuticals Incorporated) , Susan M. Cusick (Venatorx Pharmaceuticals Incorporated) , Robert E. L. Trout (Venatorx Pharmaceuticals Incorporated) , Cecilia Pozzi (University of Siena) , Filomena De Luca (University of Siena) , Manuela Benvenuti (University of Siena) , Stefano Mangani (University of Siena) , Bin Liu (Venatorx Pharmaceuticals Incorporated) , Randy W. Jackson (Venatorx Pharmaceuticals Incorporated) , Greg Moeck (Venatorx Pharmaceuticals Incorporated) , Luigi Xerri (Venatorx Pharmaceuticals Incorporated) , Christopher J. Burns (Venatorx Pharmaceuticals Incorporated) , Daniel C. Pevear (Venatorx Pharmaceuticals Incorporated) , Denis M. Daigle (Venatorx Pharmaceuticals Incorporated)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Antimicrobial Agents And Chemotherapy , VOL 64

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 8574

Open Access Open Access

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.

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Medicine, Chemistry, Biology and Bio-materials

Instruments: I04-Macromolecular Crystallography

Other Facilities: beamline ID30A-1/MASSIF-1 ESRF

Added On: 31/03/2020 08:37

Antimicrobial Agents and Chemotherapy-2020-Hamrick-e01963-19.full.pdf

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)