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Antimicrobial Agents and Chemotherapy, November 2002, p. 3692, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3692.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

Enzyme-Catalyzed Antimicrobial Activation


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LETTER
 
Li and colleagues (3) report the synthesis and properties of a cephalosporin that releases the antimicrobial agent triclosan when the ß-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 ß-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).


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REFERENCES
 
    1
  1. Hamilton-Miller, J. M. T. 1994. Dual-action antibiotic hybrids. J. Antimicrob. Chemother. 33:197-200.[Free Full Text]
    2. 2
  2. Hamilton-Miller, J. M. T. 1999. ß-lactams: variations on a chemical theme, with some surprising biological results. J. Antimicrob. Chemother. 44:729-734.[Free Full Text]
    3. 3
  3. Li, Q., J. Y. Lee, R. Castillo, M. S. Hixon, C. Pujol, V. M. Doppalapudi, H. M. Shepard, G. M. Wahl, T. J. Lobl, and M. F. Chan. 2002. NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against ß-lactamase-producing strains. Antimicrob. Agents Chemother. 46:1262-1268.[Abstract/Free Full Text]
    4. 4
  4. 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.[Abstract/Free Full Text]
    5. 5
  5. Vrudhla, V. M., H. P. Svensson, and P. D. Senter. 1995. Cephalosporin derivatives of doxorubicin as prodrugs for activation by monoclonal antibody-ß-lactamase conjugates. J. Med. Chem. 38:1380-1385.[CrossRef][Medline]
J. M. T. Hamilton-Miller*
Department of Medical Microbiology
Royal Free and University College Medical School
London NW3 2PF, United Kingdom

* Phone: 442077940500
Fax: 442074359694
E-mail: j.hamilton-miller{at}rfc.ucl.ac.uk


Author's Reply


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LETTER 
 
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 ß-lactamases to eject the 3-substituent in cephalosporins through hydrolysis of the ß-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.


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REFERENCES 
 
    1
  1. Bhargava, H. N., and P. A. Leonard. 1996. Triclosan: applications and safety. Am. J. Infect. Control 24:209-218.[CrossRef][Medline]
    2. 2
  2. Lackey, D. B., M. P. Groziak, M. Sergeeva, M. Beryt, C. Boyer, R. M. Stroud, P. Sayre, J. W. Park, P. Johnston, D. Slamon, H. M. Shepard, and M. Pegram. 2001. Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase. Biochem. Pharmacol. 61:179-189.[CrossRef][Medline]
    3. 3
  3. Li, Q., C. Boyer, J. Y. Lee, and H. M. Shepard. 2001. A novel approach to thymidylate synthase as a target for cancer chemotherapy. Mol. Pharmacol. 59:446-452.[Abstract/Free Full Text]
    4. 4
  4. Li, Q., J. Y. Lee, R. Castillo, M. S. Hixon, C. Pujol, V. R. Doppalapudi, H. M. Shepard, G. M. Wahl, T. J. Lobl, and M. F. Chan. 2002. NB2001, a novel antibacterial agent with broad-spectrum activity and enhanced potency against ß-lactamase-producing strains. Antimicrob. Agents Chemother. 46:1262-1268.
    5. 5
  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.
Qing Li*
NewBiotics, Inc.
4939 Directors Place
San Diego, CA 92121

* Phone: (858) 200-1841
Fax: (858) 200-1804
E-mail: qli{at}newbiotics.com.

Antimicrobial Agents and Chemotherapy, November 2002, p. 3692, Vol. 46, No. 11
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.11.3692.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.




This Article
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