Isolation and characterization of the inhibitors of vbacterial signal transduction

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Histidine protein kinases (HPKs) and two-component regulation are used extensively in procaryotic signal transduction processes that allow bacteria to adapt and respond to the environment. Two-component signal transduction systems are so named because at their core are two-modules, the histidine kinase and a response regulator. In response to an enviromental siganal, the kinase autophosphorylates a conserved His residue. The His-phosphate is then transferred to an aspartyl residue on the response regulator, therby altering its activity.We focused growth essentially YycF/YycG two-component system and demonstrated in vitro that YycG-YycF of Bacillus subtilis constitute two-components system and show the high specificity of the sensor protein for the cognate phosphorylation partner. Based on inhibition of YycG (histidine protein kinase) of Bacillus subtilis, newly synthesized imidazole derivatives were serched to identify antibacterial agents. NH125, NH126, and NH127 were found to virtually inhibit the incorporation of phosphate from ATP into YycG at 50 μg/ml with IC50 of 0.6-40 μM. They have also antibacterial activity in drug-resistant Staphylococcus aureus, Enterococcus, faecallis, and Streptococcus pneumoniae with MIC 0.39-6.25 μg/Ml. Furthermore, based on inhibition of such an autophosphorylation of YycG, zerumbone derivatives were serched to identify an antibacterial agent, NH0891.([2E, 6E, 10(E/Z)]-11-Bromo-4, 4, 7-trimethyl-2, 6, 10- dodecatrienoic acid).In this study, we have sown the useful and important way to develop a new class of antibacterial agents.