Journal Article

Identification of Anziaic Acid, a Lichen Depside from Hypotrachyna sp., as a New Topoisomerase Poison Inhibitor

Tse-Dinh, Yuk-Ching, Annamalai, Thirunavukkarasu, Cao, Shugeng, Clardy, Jon, Tamayo-Castillo, Giselle, Cheng, Bokun, Vasquez, Victor

2013

Overview

Topoisomerase inhibitors are effective for antibacterial and anticancer therapy because they can lead to the accumulation of the intermediate DNA cleavage complex formed by the topoisomerase enzymes, which trigger cell death. Here we report the application of a novel enzyme-based high-throughput screening assay to identify natural product extracts that can lead to increased accumulation of the DNA cleavage complex formed by recombinant Yersinia pestis topoisomerase I as part of a larger effort to identify new antibacterial compounds. Further characterization and fractionation of the screening positives from the primary assay led to the discovery of a depside, anziaic acid, from the lichen Hypotrachyna sp. as an inhibitor for both Y. pestis and Escherichia coli topoisomerase I. In in vitro assays, anziaic acid exhibits antibacterial activity against Bacillus subtilis and a membrane permeable strain of E. coli. Anziaic acid was also found to act as an inhibitor of human topoisomerase II but had little effect on human topoisomerase I. This is the first report of a depside with activity as a topoisomerase poison inhibitor and demonstrates the potential of this class of natural products as a source for new antibacterial and anticancer compounds.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Accumulation / Acids / Anti-Bacterial Agents - isolation & purification / Anti-Bacterial Agents - pharmacology / Anti-Bacterial Agents - toxicity / Antibacterial activity / Antibacterial agents / Antibacterial materials / Anticancer properties / Antiinfectives and antibacterials / Antimicrobial agents / Apoptosis / Ascomycota - chemistry / Assaying / Biochemistry / Biological products / Biological Products - pharmacology / Biology / Cancer / Cell death / Cell Survival - drug effects / Chemistry / Cleavage / Deoxyribonucleic acid / Depsides - isolation & purification / Depsides - pharmacology / Depsides - toxicity / Detergents - pharmacology / DNA / DNA topoisomerase / DNA topoisomerase (ATP-hydrolysing) / DNA Topoisomerases, Type I - metabolism / Dose-Response Relationship, Drug / Drug Evaluation, Preclinical / E coli / Enzymes / Escherichia coli / Escherichia coli - drug effects / Escherichia coli - enzymology / Fractionation / High-throughput screening / High-Throughput Screening Assays / Humans / Hydroxybenzoates - isolation & purification / Hydroxybenzoates - pharmacology / Hydroxybenzoates - toxicity / Identification / Inhibitors / Library collections / Lichens / Magnesium - pharmacology / Medicine / Molecular biology / Mutation / Natural products / Poisons / Screening / Small Molecule Libraries - pharmacology / Topoisomerase Inhibitors - isolation & purification / Topoisomerase Inhibitors - pharmacology / Topoisomerase Inhibitors - toxicity / Yersinia pestis - drug effects / Yersinia pestis - enzymology