Inhibition of Dna Topoisomerases by Microbial Inhibitors

Abstract

New inhibitors of DNA topoisomerase named 2280-DTI and 2890-DTI have been discovered in the culture filtrates of Micromonospora sp. strain No. 2280 and Streptomyces sp. strain No. 2890, respectively. Both inhibitors were purified from each culture filtrate by column chromatography on Diaion, Dowex and gel filtration. Both inhibitors were thermostable acidic substances with high molecular weight and inhibited topoisomerase I in a non-competitive manner. They differed from well-known inhibitors of topoisomerases such as camptothecin and doxorubicin, which inhibit the DNA rejoining reaction of the enzyme by intercalation into DNA strands or stabilizing the cleavable complex (enzyme-DNA reaction intermediate). 2280-DTI and 2890-DTI did not intercalate into DNA strands and also had no ability to stabilize the cleavable complex. It is suggested that 2280-DTI and 2890-DTI inhibit the DNA breaking and rejoining reactions of topoisomerase by direct action on the enzyme molecule.

Key Words:

• DNA topoisomerase inhibitor
• Micromonospora
• Streptomyces
• 2280-DTI
• 2890-DTI