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

Hamrick, J. C.; Docquier, Jean-Denis; Uehara, T.; Myers, C. L.; Six, D. A.; Chatwin, C. L.; John, K. J.; Vernacchio, S. F.; Cusick, S. M.; Trout, R. E. L.; Pozzi, C.; De Luca, F.; Benvenuti, M.; Mangani, S.; Liu, B.; Jackson, R. W.; Moeck, G.; Xerri, L.; Burns, C. J.; Pevear, D. C.; Daigle, D. M.

doi:10.1128/AAC.01963-19

Article (Scientific journals)

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

Hamrick, J. C.; Docquier, Jean-Denis; Uehara, T. et al.

2020 • In Antimicrobial Agents and Chemotherapy, 64 (3)

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/252538

DOI
10.1128/AAC.01963-19

PubMed
31871094

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Keywords :

Antibacterial; Biochemistry; Microbiology; Structural biology; Article; Escherichia coli; Pseudomonas aeruginosa

Abstract :

[en] 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 metalloβ-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. Copyright © 2020 Hamrick et al.

Disciplines :

Microbiology

Author, co-author :

Hamrick, J. C.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Docquier, Jean-Denis ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines

Uehara, T.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Myers, C. L.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Six, D. A.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Chatwin, C. L.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

John, K. J.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Vernacchio, S. F.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Cusick, S. M.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

Trout, R. E. L.; Venatorx Pharmaceuticals Incorporated, Malvern, PA, United States

More authors (11 more)

Language :

English

Title :

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

Publication date :

2020

Journal title :

Antimicrobial Agents and Chemotherapy

ISSN :

0066-4804

eISSN :

1098-6596

Publisher :

American Society for Microbiology

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

NIAID - National Institute of Allergy and Infectious Diseases
Wellcome Trust

Available on ORBi :

since 13 November 2020

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