Identification of a Dithiazoline Inhibitor of Escherichia colil,d-Carboxypeptidase A

• Published in: Antimicrobial agents and chemotherapy Vol. 49; no. 11; pp. 4500 - 4507
• Main Authors: Baum, Ellen Z, Crespo-Carbone, Steven M, Foleno, Barbara, Peng, Sean, Hilliard, Jamese J, Abbanat, Darren, Goldschmidt, Raul, Bush, Karen
• Format: Journal Article
• Language: English
• Published: American Society for Microbiology 01.11.2005
• Subjects: Anti-Bacterial Agents; Carboxypeptidases A; Escherichia coli; Mechanisms of Action: Physiological Effects; Protease Inhibitors; Thiazoles
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.49.11.4500-4507.2005

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.