FEBS Letters 2005-04-11

Targeting protein homodimerization: a novel drug discovery system.

Eiji Furuta, Kaneyoshi Yamamoto, Daisuke Tatebe, Kounosuke Watabe, Takashi Kitayama, Ryutaro Utsumi

Index: FEBS Lett. 579(10) , 2065-70, (2005)

Full Text: HTML

Abstract

To identify a novel class of antibiotics, we have developed a high-throughput genetic system for targeting the homodimerization (HD system) of histidine kinase (HK), which is essential for a bacterial signal transduction system (two-component system, TCS). By using the HD system, we screened a chemical library and identified a compound, I-8-15 (1-dodecyl-2-isopropylimidazole), that specifically inhibited the dimerization of HK encoded by the YycG gene of Staphylococcus aureus and induced concomitant bacterial cell death. I-8-15 also showed antibacterial activity against MRSA (methicillin-resistant S. aureus) and VRE (vancomycin-resistant Enterococcus faecalis) with MICs at 25 and 50 microg/ml, respectively.