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Antimicrobial Agents and Chemotherapy, February 2004, p. 477-483, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.477-483.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mechanism of Action of NB2001 and NB2030, Novel Antibacterial Agents Activated by ß-Lactamases

Geoffrey W. Stone,* Qin Zhang, Rosario Castillo, V. Ramana Doppalapudi, Analia R. Bueno, Jean Y. Lee, Qing Li, Maria Sergeeva, Gody Khambatta, and Nafsika H. Georgopapadakou

NewBiotics, Inc., San Diego, California 92121

Received 12 May 2003/ Returned for modification 1 September 2003/ Accepted 2 November 2003

Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compounds, NB2001 and NB2030, contain a cephalosporin with a thienyl (NB2001) or a tetrazole (NB2030) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compounds exploit ß-lactamases to release triclosan through hydrolysis of the ß-lactam ring. Like cephalothin, NB2001 and NB2030 were hydrolyzed by class A ß-lactamases (Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C ß-lactamases (Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies (kcat/Km). They also bound to the penicillin-binding proteins of S. aureus and E. coli, but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphology in E. coli consistent with the toxophore rather than the ß-lactam being responsible for antibacterial activity. In biochemical assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concentrations being markedly reduced relative to that of free triclosan. The transport of NB2001, NB2030, and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli. Taken together, the results suggest that NB2001 and NB2030 act primarily as triclosan prodrugs in S. aureus and E. coli.

* Corresponding author. Present address: Department of Medicine 0169, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0679. Phone: (858) 552-8585, ext. 7203. E-mail: gstone{at}ucsd.edu.

Antimicrobial Agents and Chemotherapy, February 2004, p. 477-483, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.477-483.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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