Use of combinatorial library screening to identify inhibitors of a bacterial two-component signal transduction kinase

Bacterial resistance to antibiotics is emerging as amajor concern to the medical community. Theappearance of several antibiotic-resistant strains,including multidrug-resistant Staphylococcusaureus, raises the prospect that infections by thesebacteria could soon become untreatable with currentlyavailable antibiotics. In order to address thisproblem, increased emphasis is being placed on thediscovery of novel classes of antibacterial agentsthat inhibit novel molecular targets using sources ofcompounds not yet exploited for antibiotic drugdiscovery. Novel classes of compounds can now berapidly investigated using combinatorial chemistryapproaches. This report describes the identificationof novel antibacterial compounds from a combinatoriallibrary of N-acetylated, C-amidated D-amino acidhexapeptides. This library of compounds was screenedfor inhibitors of CheA, a member of the bacterialtwo-component signal transduction kinase family. Several peptides with apparent IC₅₀ values in thelow micromolar range were identified. In addition toinhibiting CheA, these peptides inhibited mammalianprotein kinase C (from rat brain) with comparablepotency. Finally, these peptides were also found tohave significant antibacterial properties, althoughthe true mechanism by which they exhibited inhibitionof bacterial growth remains uncertain.