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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
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

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
Documents:
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)