Identification of the aminocatechol A-3253 as an in vitro poison of DNA topoisomerase I from Candida albicans.
The aminocatechol A-3253 is active against several pathogenic fungi, including Candida albicans, Cryptococcus albidus, and Aspergillus niger. A-3253 interferes with both the in vitro biosynthesis of (1,3)-beta-glucan and the activity of topoisomerases I isolated from Candida spp. It is likely that one or more of the enzymes involved in glucan biosynthesis rather than topoisomerase I is the primary intracellular target of A-3253, since a strain of Saccharomyces cerevisiae lacking topoisomerase I is as susceptible to A-3253 as cells containing wild-type levels of topoisomerase I. However, the interaction of A-3253 with topoisomerase I in vitro is of interest since the Candida topoisomerase is more susceptible to A-3253 than is the topoisomerase I isolated from human HeLa cells. A-3253 is both a reversible inhibitor of topoisomerase I catalysis and a reversible poison of topoisomerase I, and in both reactions the fungal topoisomerase I is more susceptible than the human topoisomerase I to A-3253. In contrast, an earlier study found that the human topoisomerase I is more susceptible than the fungal topoisomerase to camptothecin (J. M. Fostel, D. A. Montgomery, and L. L. Shen, Antimicrob. Agents Chemother. 36:2131-2138, 1992). Taken together with the response to camptothecin, the greater susceptibility of the Candida topoisomerase I to A-3253 suggests that there are structural differences between the human and fungal type I topoisomerases which can likely be exploited to allow for the development of antifungal agents which act against the fungal topoisomerase and which have minimal activity against the human enzyme.
Fostel
J
J
Anti-Infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Montgomery
D
D
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D002384:Catalysis; D002395:Catecholamines / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002686:Chitin / Q000096:biosynthesis; D004271:DNA, Fungal / Q000187:drug effects / Q000378:metabolism; D005936:Glucans / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000935:Antifungal Agents; D002395:Catecholamines; D004271:DNA, Fungal; D005936:Glucans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C026669:4-aminocatechol; D002686:Chitin