Targeting protein homodimerization: a novel drug discovery system

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

doi:10.1016/j.febslet.2005.02.056

Targeting protein homodimerization: a novel drug discovery system

FEBS Lett. 2005 Apr 11;579(10):2065-70. doi: 10.1016/j.febslet.2005.02.056.

Authors

Eiji Furuta¹, Kaneyoshi Yamamoto, Daisuke Tatebe, Kounosuke Watabe, Takashi Kitayama, Ryutaro Utsumi

Affiliation

¹ Department of Bioscience and Biotechnology, Graduate School of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.

PMID: 15811319
DOI: 10.1016/j.febslet.2005.02.056

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
DNA Primers
Dimerization
Drug Design
Histidine Kinase
Protein Kinases / chemistry
Proteins / chemistry*

Substances

DNA Primers
Proteins
Protein Kinases
Histidine Kinase