VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime in
| Autor: | Jodie C, Hamrick, Jean-Denis, Docquier, Tsuyoshi, Uehara, Cullen L, Myers, David A, Six, Cassandra L, Chatwin, Kaitlyn J, John, Salvador F, Vernacchio, Susan M, Cusick, Robert E L, Trout, Cecilia, Pozzi, Filomena, De Luca, Manuela, Benvenuti, Stefano, Mangani, Bin, Liu, Randy W, Jackson, Greg, Moeck, Luigi, Xerri, Christopher J, Burns, Daniel C, Pevear, Denis M, Daigle |
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| Rok vydání: | 2019 |
| Předmět: |
microbiology
Carboxylic Acids β-lactams β-lactamases Microbial Sensitivity Tests biochemical phenomena metabolism and nutrition Clinical Therapeutics bacterial infections and mycoses Editor's Pick Protein Structure Secondary Anti-Bacterial Agents antibacterial Bacterial Proteins Pseudomonas aeruginosa polycyclic compounds bacteria biochemistry structural biology Borinic Acids Cefepime beta-Lactamase Inhibitors |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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