title: Identification of a dithiazoline inhibitor of Escherichia coli L,D-carboxypeptidase A.
abstract: 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 microM. 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869, USA. ebaum@prdus.jnj.com
authors.forename: Ellen Z
authors.initials: EZ
authors.lastname: Baum
authors.forename: Steven M
authors.initials: SM
authors.lastname: Crespo-Carbone
authors.forename: Barbara
authors.initials: B
authors.lastname: Foleno
authors.forename: Sean
authors.initials: S
authors.lastname: Peng
authors.forename: Jamese J
authors.initials: JJ
authors.lastname: Hilliard
authors.forename: Darren
authors.initials: D
authors.lastname: Abbanat
authors.forename: Raul
authors.initials: R
authors.lastname: Goldschmidt
authors.forename: Karen
authors.initials: K
authors.lastname: Bush
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors*; D004755:Enterobacteriaceae / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D011480:Protease Inhibitors; D013844:Thiazoles; D043422:Carboxypeptidases A