Use of combinatorial library screening to identify inhibitors of a bacterial two-component signal transduction kinase
Siddhartha Roychoudhury, Sylvie E. Blondelle, Susan M. Collins, Michael C. Davis, Helana D. McKeever, Richard A. Houghten, Christian N. Parker
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 IC_50
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.
Keywords
antibacterial compounds, bacterial signal transduction, CheA,
combinatorial chemistry, deconvolution, enzyme inhibition, histidine
protein kinase, synthetic peptides
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