Targeting protein homodimerization: a novel drug discovery system.
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.
Furuta
Eiji
E
Department of Bioscience and Biotechnology, Graduate School of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
Yamamoto
Kaneyoshi
K
Tatebe
Daisuke
D
Watabe
Kounosuke
K
Kitayama
Takashi
T
Utsumi
Ryutaro
R
D001483:Base Sequence; D017931:DNA Primers; D019281:Dimerization; D015195:Drug Design; D000071677:Histidine Kinase; D011494:Protein Kinases / Q000737:chemistry; D011506:Proteins / Q000737:chemistry*
D017931:DNA Primers; D011506:Proteins; D011494:Protein Kinases; D000071677:Histidine Kinase