NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against beta-lactamase-producing strains

Antimicrob Agents Chemother. 2002 May;46(5):1262-8. doi: 10.1128/AAC.46.5.1262-1268.2002.


Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. beta-Lactamase overexpression is a common mechanism of bacterial resistance to beta-lactam antibiotics. We present here the results for one of the beta-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional beta-lactam antibiotics, where hydrolysis of the beta-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by beta-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 beta-lactamase, forming triclosan with a second-order rate constant (k(cat)/K(m)) of greater than 77,000 M-1 s-1. (ii) Triclosan is detected in NB2001-treated, beta-lactamase-producing Escherichia coli but not in E. coli that does not express beta-lactamase. (iii) NB2001 activity against beta-lactamase-producing E. coli is decreased in the presence of the beta-lactamase inhibitor clavulanic acid. NB2001 was similar to or more potent than reference antibiotics against clinical isolates of Staphylococcus aureus (including MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Moraxella catarrhalis and Haemophilus influenzae. NB2001 is also active against Klebsiella pneumoniae, Enterobacter aerogenes, and Enterobacter cloacae. The results indicate that NB2001 is a potent, broad-spectrum antibacterial agent and demonstrate the potential of ECTA in overcoming beta-lactamase-mediated resistance.

MeSH terms

  • Bacterial Infections / microbiology
  • Cephalosporins / chemistry
  • Cephalosporins / metabolism
  • Cephalosporins / pharmacology*
  • Drug Design
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Gram-Negative Bacteria / drug effects*
  • Gram-Positive Bacteria / drug effects*
  • Humans
  • Hydrolysis
  • Microbial Sensitivity Tests
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Triclosan / analogs & derivatives
  • Triclosan / chemistry
  • Triclosan / metabolism
  • Triclosan / pharmacology*
  • beta-Lactamases / metabolism*


  • Cephalosporins
  • NB 2001
  • Prodrugs
  • Triclosan
  • beta-Lactamases
  • beta-lactamase TEM-1