NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against...

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.