Comparison of responses of DNA topoisomerase I from Candida albicans and human cells to four new agents which stimulate topoisomerase-dependent DNA nicking.
DNA topoisomerase I is a potential target for therapeutic antifungal agents predicted to have a fungicidal mode of action. This report describes four agents with varying degrees of selectivity for the fungal topoisomerase I compared to the human enzyme: 5-hydroxy-1H-indole-3-acetic acid (5-HIAA), quinizarin, dibenzo-p-dioxin-2-carboxylic acid and 7-amino-4-hydroxy-2-naphthalenesulfonic acid. Taken together with the response of topoisomerase to camptothecin and aminocatechol, these data suggest that there are sufficient structural differences between the topoisomerase I from Candida albicans and human cells to allow selective targeting of the fungal topoisomerase I over its human counterpart.
Fostel
J
J
Anti-Infective Research Division, Abbott Labs., Abbott Park, IL 60064, USA. fostel.jennifer@igate.abbott.com
Montgomery
D
D
Lartey
P
P
D000880:Anthraquinones / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D002176:Candida albicans / Q000201:enzymology*; D002395:Catecholamines / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism*; D004147:Dioxins / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000494:pharmacology; D009282:Naphthalenesulfonates / Q000494:pharmacology; D013045:Species Specificity
D000880:Anthraquinones; D000935:Antifungal Agents; D002395:Catecholamines; D004147:Dioxins; D009282:Naphthalenesulfonates; C103886:dibenzo-1,4-dioxin-2-carboxylic acid; C026669:4-aminocatechol; D006897:Hydroxyindoleacetic Acid; C103885:7-amino-4-hydroxy-2-naphthalenesulfonic acid; C034890:1,4-dihydroxyanthraquinone; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin