CJ-12,371 AND CJ-12,372, 2 NOVEL DNA GYRASE INHIBITORS FERMENTATION, ISOLATION, STRUCTURAL ELUCIDATION AND BIOLOGICAL-ACTIVITIES

A fermentation broth of an unidentified fungus (N983-46) was found to produce DNA gyrase inhibitors, CJ-12,371 (1) and CJ-12,372 (2). Follow ing isolation by solvent extraction and silica gel and ODS (reverse ph ase) chromatographies, the structures were determined to be novel spir o-ketal compounds with S-configuration at position C-1. CJ-12,371 and CJ-12,372 inhibit both DNA supercoiling and relaxation mediated by Esc herichia coli DNA gyrase. The interaction of these compounds with DNA gyrase appears to be novel in that the compounds inhibit supercoiling and relaxation without blocking religation; thus, no cleavage intermed iate of double strand DNA is observed. Both compounds have antibacteri al activity against several species of pathogenic Gram-positive bacter ia, with MICs between 25 and 100 mu g/ml. These results suggest that t he antibacterial potency of CJ-12,371 and CJ-12,372 is attributed to t he inhibition of DNA gyrase. However, the compounds did not inhibit DN A gyrase selectively, as they also inhibited eukaryotic topoisomerase II-mediated relaxation. Semi-synthetic modifications to the dihydroxy motif in CJ-12,371 altered both gyrase- and topoisomerase II-inhibitor y activities, but did not enhance selectivity.