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Volume 4, Issue 3, 1998, pp. 173-182

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

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.

antibacterial compounds, bacterial signal transduction, CheA, combinatorial chemistry, deconvolution, enzyme inhibition, histidine protein kinase, synthetic peptides

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