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Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors.

Nakita ReddyLetisha GirdhariMbongeni ShungubeArno Christiaan GouwsByron K PetersKamal K RajbongshiSooraj BajinathSipho MdandaThandokuhle NtombelaThilona ArumugamLinda A BesterSanil D SinghAnil Amichund ChuturgoonPer I ArvidssonGlenn E M MaguireHendrik Gerhardus KrugerThavendran GovenderTricia Naicker
Published in: Antibiotics (Basel, Switzerland) (2023)
Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-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 (K i app ) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-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 log 10 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).
Keyphrases
  • gram negative
  • multidrug resistant
  • klebsiella pneumoniae
  • escherichia coli
  • drug resistant
  • acinetobacter baumannii
  • infectious diseases
  • genome wide
  • cancer therapy