title: Use of combinatorial library screening to identify inhibitors of a bacterial two-component signal transduction kinase.
abstract: Bacterial resistance to antibiotics is emerging as a major concern to the medical community. The appearance of several antibiotic-resistant strains, including multidrug-resistant Staphylococcus aureus, raises the prospect that infections by these bacteria could soon become untreatable with currently available antibiotics. In order to address this problem, increased emphasis is being placed on the discovery of novel classes of antibacterial agents that inhibit novel molecular targets using sources of compounds not yet exploited for antibiotic drug discovery. Novel classes of compounds can now be rapidly investigated using combinatorial chemistry approaches. This report describes the identification of novel antibacterial compounds from a combinatorial library of N-acetylated, C-amidated D-amino acid hexapeptides. This library of compounds was screened for inhibitors of CheA, a member of the bacterial two-component signal transduction kinase family. Several peptides with apparent IC50 values in the low micromolar range were identified. In addition to inhibiting CheA, these peptides inhibited mammalian protein kinase C (from rat brain) with comparable potency. Finally, these peptides were also found to have significant antibacterial properties, although the true mechanism by which they exhibited inhibition of bacterial growth remains uncertain.
authors.affiliation: Procter and Gamble Pharmaceuticals-Research Division, Health Care Research Center, Mason, OH 45040, USA. roychoudhury.s@pg.com
authors.forename: S
authors.initials: S
authors.lastname: Roychoudhury
authors.forename: S E
authors.initials: SE
authors.lastname: Blondelle
authors.forename: S M
authors.initials: SM
authors.lastname: Collins
authors.forename: M C
authors.initials: MC
authors.lastname: Davis
authors.forename: H D
authors.initials: HD
authors.lastname: McKeever
authors.forename: R A
authors.initials: RA
authors.lastname: Houghten
authors.forename: C N
authors.initials: CN
authors.lastname: Parker
mesh_terms: D000596:Amino Acids; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001426:Bacterial Proteins; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D000072236:Methyl-Accepting Chemotaxis Proteins; D019151:Peptide Library
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins; D000072236:Methyl-Accepting Chemotaxis Proteins; D019151:Peptide Library