Details

Autor(en) / Beteiligte

• Hamrick, Jodie C
• Docquier, Jean-Denis
• Uehara, Tsuyoshi
• Myers, Cullen L
• Six, David A
• Chatwin, Cassandra L
• John, Kaitlyn J
• Vernacchio, Salvador F
• Cusick, Susan M
• Trout, Robert E L
• Pozzi, Cecilia
• De Luca, Filomena
• Benvenuti, Manuela
• Mangani, Stefano
• Liu, Bin
• Jackson, Randy W
• Moeck, Greg
• Xerri, Luigi
• Burns, Christopher J
• Pevear, Daniel C
• Daigle, Denis M

Titel

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

Ist Teil von

• Antimicrobial agents and chemotherapy, 2020-02, Vol.64 (3)

Ort / Verlag

United States: American Society for Microbiology

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Electronic Journals Library - Freely accessible e-journals

Beschreibungen/Notizen

• As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant (CRE) and carbapenem-resistant (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 ( ) 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 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 clinical isolates tested and 38/41 clinical isolates tested with MIC s 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.