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Antimicrobial Agents and Chemotherapy, November 2005, p. 4500-4507, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4500-4507.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Identification of a Dithiazoline Inhibitor of Escherichia coli L,D-Carboxypeptidase A

Ellen Z. Baum,* Steven M. Crespo-Carbone, Barbara Foleno, Sean Peng, Jamese J. Hilliard, Darren Abbanat, Raul Goldschmidt, and Karen Bush

Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey 08869

Received 13 May 2005/ Returned for modification 5 July 2005/ Accepted 18 August 2005

The enzyme L,D-carboxypeptidase A is involved in the recycling of bacterial peptidoglycan and is essential in Escherichia coli during stationary phase. By high-throughput screening, we have identified a dithiazoline inhibitor of the enzyme with a 50% inhibitory concentration of 3 µM. The inhibitor appeared to cause lysis of E. coli during stationary phase, behavior that is similar to a previously described deletion mutant of L,D-carboxypeptidase A (M. F. Templin, A. Ursinus, and J.-V. Holtje, EMBO J. 18:4108-4117, 1999). As much as a one-log drop in CFU in stationary phase was observed upon treatment of E. coli with the inhibitor, and the amount of intracellular tetrapeptide substrate increased by approximately 33%, consistent with inhibition of the enzyme within bacterial cells. Stationary-phase targets such as L,D-carboxypeptidase A are largely underrepresented as targets of the antibiotic armamentarium but provide potential opportunities to interfere with bacterial growth and persistence.

* Corresponding author. Mailing address: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, NJ 08869. Phone: (908) 704-4320. Fax: (908) 707-3501. E-mail: ebaum{at}prdus.jnj.com.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4500-4507, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4500-4507.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Park, J. T., Uehara, T. (2008). How Bacteria Consume Their Own Exoskeletons (Turnover and Recycling of Cell Wall Peptidoglycan). Microbiol. Mol. Biol. Rev. 72: 211-227 [Abstract] [Full Text]  
  • Baum, E. Z., Crespo-Carbone, S. M., Abbanat, D., Foleno, B., Maden, A., Goldschmidt, R., Bush, K. (2006). Utility of Muropeptide Ligase for Identification of Inhibitors of the Cell Wall Biosynthesis Enzyme MurF. Antimicrob. Agents Chemother. 50: 230-236 [Abstract] [Full Text]  


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