Fostel J, Montgomery D
Anti-Infective Research Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Antimicrob Agents Chemother. 1995 Mar;39(3):586-92. doi: 10.1128/AAC.39.3.586.
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.
氨基儿茶酚A - 3253对多种致病真菌具有活性，包括白色念珠菌、浅白隐球菌和黑曲霉。A - 3253既干扰（1,3）-β-葡聚糖的体外生物合成，也干扰从念珠菌属分离的拓扑异构酶I的活性。A - 3253的主要细胞内靶点可能是参与葡聚糖生物合成的一种或多种酶，而非拓扑异构酶I，因为缺乏拓扑异构酶I的酿酒酵母菌株对A - 3253的敏感性与含有野生型水平拓扑异构酶I的细胞相同。然而，A - 3253与拓扑异构酶I在体外的相互作用值得关注，因为念珠菌拓扑异构酶比从人宫颈癌细胞系（HeLa细胞）分离的拓扑异构酶I对A - 3253更敏感。A - 3253既是拓扑异构酶I催化作用的可逆抑制剂，也是拓扑异构酶I的可逆毒剂，在这两种反应中，真菌拓扑异构酶I比人拓扑异构酶I对A - 3253更敏感。相比之下，一项早期研究发现人拓扑异构酶I比真菌拓扑异构酶对喜树碱更敏感（J.M.福斯特尔、D.A.蒙哥马利和L.L.沈，《抗菌药物化疗》36:2131 - 2138，1992）。结合对喜树碱的反应，念珠菌拓扑异构酶I对A - 3253更高的敏感性表明，人和真菌I型拓扑异构酶之间存在结构差异，这可能有助于开发针对真菌拓扑异构酶且对人酶活性最小的抗真菌药物。
