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NB2001, a Novel Antibacterial Agent with Broad-Spectrum Activity and Enhanced Potency against ß-Lactamase-Producing Strains

Qing Li,^1* Jean Y. Lee,¹ Rosario Castillo,¹ Mark S. Hixon,¹ Catherine Pujol,¹ Venkata Ramana Doppalapudi,¹ H. Michael Shepard,¹ Geoffrey M. Wahl,² Thomas J. Lobl,¹ and Ming Fai Chan^1,

NewBiotics, Inc., San Diego, California 92121,¹ Salk Institute, La Jolla, California 92037-1099²

Received 16 April 2001/ Returned for modification 26 July 2001/ Accepted 18 January 2002

Enzyme-catalyzed therapeutic activation (ECTA) is a novel prodrug strategy to overcome drug resistance resulting from enzyme overexpression. ß-Lactamase overexpression is a common mechanism of bacterial resistance to ß-lactam antibiotics. We present here the results for one of the ß-lactamase ECTA compounds, NB2001, which consists of the antibacterial agent triclosan in a prodrug form with a cephalosporin scaffold. Unlike conventional ß-lactam antibiotics, where hydrolysis of the ß-lactam ring inactivates the antibiotic, hydrolysis of NB2001 by ß-lactamase releases triclosan. Evidence supporting the proposed mechanism is as follows. (i) NB2001 is a substrate for TEM-1 ß-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, ß-lactamase-producing Escherichia coli but not in E. coli that does not express ß-lactamase. (iii) NB2001 activity against ß-lactamase-producing E. coli is decreased in the presence of the ß-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 ß-lactamase-mediated resistance.

Present address: Palomar Research, Inc., Encinitas, CA 92093-1989.

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