title: Role of the C(1) Triol Group in Bicyclomycin: Synthesis and Biochemical and Biological Properties.
abstract: Bicyclomycin (1) is a commercial antibiotic whose primary site of action in Escherichia coli is the essential cellular protein transcription termination factor rho. The bicyclomycin binding domain in rho is unknown; however, enzyme irreversible inactivators that modify rho upon activation may identify the site. In this study, we investigated the importance for rho binding of the C(1) triol group in 1. Twelve bicyclomycin derivatives were prepared, and the C(1) triol group was modified at the C(1'), the C(2'), and the C(3') sites. The compounds were evaluated by rho-dependent ATPase and transcription termination assays and their antimicrobial activities assessed using a filter disc assay. Bicyclomycin inhibited both rho-dependent ATPase (I(50) = 60 &mgr;M) and rho-dependent transcription termination (I(50) approximately 5 &mgr;M) processes and had a minimum inhibitory concentration value of 0.25 mg/mL against E. coli W3350 cells. None of the 12 C(1) triol bicyclomycin derivatives significantly inhibited rho-dependent ATPase (I(50) > 400 &mgr;M) and transcription termination (I(50) > 100 &mgr;M) activities or exhibited antibiotic activity at a 32 mg/mL concentration. These results indicated that there was a strong molecular complement between the C(1) triol group and its rho binding site. We concluded that the C(1) triol group in 1 is a critical structural element necessary for drug binding to rho and that an enzyme irreversible inactivating unit placed at this site would prohibit the bicyclomycin derivative from efficiently binding to rho.
authors.affiliation: Department of Chemistry, University of Houston, Houston, Texas 77204-5641, and Department of Biochemical and Biophysical Sciences, University of Houston, Houston, Texas 77204-5934.
authors.forename: Hyeung-geun
authors.lastname: Park Hg
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Zhang
authors.forename: William R.
authors.initials: WR
authors.lastname: Widger
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn