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. 2002 Nov;46(11):3692. doi: 10.1128/AAC.46.11.3692.2002

Enzyme-Catalyzed Antimicrobial Activation

J M T Hamilton-Miller 1,*
PMCID: PMC128745  PMID: 12384397

Li and colleagues (3) report the synthesis and properties of a cephalosporin that releases the antimicrobial agent triclosan when the β-lactam bond is enzymatically hydrolyzed and describe this concept as a “novel prodrug strategy to overcome drug resistance.” This claim of novelty must not be allowed to go unchallenged. As long ago as 1976, scientists from Glaxo in the United Kingdom (4) described a precisely analogous compound, the cephalosporin MCO, that ejected the antimicrobial compound pyrithione (“Omadine”) when an organism producing β-lactamase was encountered. Since then, there have been several other compounds synthesized with this antimicrobial strategy in mind, based on cephalosporins, carbapenems, and penems, as detailed in reviews (1, 2). A more recent development has been to harness this property of the cephalosporin nucleus as a potential targeting mechanism for anticancer drugs (5).

REFERENCES

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Antimicrob Agents Chemother. 2002 Nov;46(11):3692.

Author's Reply

Qing Li 1,*

Enzyme-catalyzed therapeutic activation (ECTA) is a general approach developed at NewBiotics to produce new pharmaceuticals that transform drug resistance into a therapeutic advantage in the treatment of cancer (2, 3) and infectious disease. In our paper (4), the term “novel” refers to NB2001 itself and to the general ECTA concept, not to the concept of utilizing β-lactamases to eject the 3-substituent in cephalosporins through hydrolysis of the β-lactam ring (5). In this respect, Prof. Hamilton-Miller is correct and we thank him for prompting this clarification. NB2001 is a chemically stable compound that employs triclosan, a potent, broad-spectrum antibacterial agent whose activity is blocked until it is released from the cephalosporin. Significantly, NB2001 has reduced toxicity relative to that of triclosan (50% lethal dose [LD50], >100 mg/kg of body weight [unpublished data] versus an LD50 of 19 mg/kg in mice by intravenous injection [1]), which highlights one of the benefits of the ECTA approach.

REFERENCES

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  • 5.O'Callaghan, C. H., R. B. Sykes, and S. E. Staniforth. 1976. A new cephalosporin with a dual mode of action. Antimicrob. Agents Chemother. 10:245-248. [DOI] [PMC free article] [PubMed] [Google Scholar]

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