Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel ß-Lactam-Metallo-ß-Lactamase Inhibitors.
Antibiotics (Basel)
; 12(4)2023 Mar 23.
Article
in English
| MEDLINE | ID: covidwho-2302399
ABSTRACT
Virulent Enterobacterale strains expressing serine and metallo-ß-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop ß-lactamase inhibitors to counter this resistance. Currently, serine ß-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-ß-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived ß-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-ß-lactamase (NDM-1) and Verona Integron-encoded Metallo-ß-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Experimental Studies
/
Prognostic study
Language:
English
Year:
2023
Document Type:
Article
Affiliation country:
Antibiotics12040633
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