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Potent inhibitory activity of taniborbactam towards NDM-1 and NDM-1 Q119X mutants, and in vitro activity of cefepime/taniborbactam against MBLs producing Enterobacterales.
- Source :
-
International journal of antimicrobial agents [Int J Antimicrob Agents] 2021 Jan; Vol. 57 (1), pp. 106228. Date of Electronic Publication: 2020 Nov 24. - Publication Year :
- 2021
-
Abstract
- Objective: This study aimed to investigate the in vitro activity of taniborbactam (VNRX-5133), a novel broad-spectrum bicyclic boronate, against NDM-1 and Q119E, Q119K, Q119C, Q119F, Q119V, and Q119Y NDM-1 variants, which showed an increased activity towards some β-lactams, including cefepime.<br />Methods: Inhibition kinetic assays were spectrophotometrically performed using cefepime (50 μM) as the reporter substrate and 80 nM of each enzyme. Taniborbactam behaves as a competitive inhibitor towards NDM-1 and NDM-1 Q119 variants with lower Ki values (range 3-16 nM). The phenotypic profile was assessed in both Enterobacterales clinical isolates and engineered Escherichia coli BL21(DE3) strains by conventional broth microdilution procedures according to the Clinical and Laboratory Standards Institute (CLSI).<br />Results: Taniborbactam at a fixed concentration of 4 mg/L was able to restore activity of cefepime in 24 of 26 Enterobacterales clinical isolates harbouring metallo-β-lactamases with MIC <subscript>50</subscript> /MIC <subscript>90</subscript> values of 14 mg/L. Cefepime MICs were drastically reduced in all clinical isolates and in NDM-1 and Q119X producing Escherichia coli BL21(DE3). Taniborbactam was unable to restore susceptibility to cefepime in two IMP variants producing clinical isolates.<br />Conclusion: The inhibition level of NDM enzymes provided by taniborbactam protects the antibacterial activity of cefepime from this important metallo-β-lactamase.<br /> (Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)
- Subjects :
- Anti-Bacterial Agents pharmacology
Drug Contamination
Drug Synergism
Enterobacteriaceae metabolism
Microbial Sensitivity Tests
beta-Lactamases
Borinic Acids pharmacology
Carboxylic Acids pharmacology
Cefepime pharmacology
Drug Resistance, Bacterial drug effects
Enterobacteriaceae drug effects
beta-Lactamase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7913
- Volume :
- 57
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- International journal of antimicrobial agents
- Publication Type :
- Academic Journal
- Accession number :
- 33246038
- Full Text :
- https://doi.org/10.1016/j.ijantimicag.2020.106228