Activity of Hoechst 33258 against Pneumocystis carinii f. sp muris, Candida albicans, and Candida dubliniensis
Activity of Hoechst 33258 against Pneumocystis carinii f. sp muris, Candida albicans, and Candida dubliniensis
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DOI：
10.1128/aac.49.4.1326-1330.2005
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发表时间：
2005-04-01
影响因子：
4.9
通讯作者：
Gigliotti, F
中科院分区：
文献类型：
--
作者：
Disney, MD;Stephenson, R;Gigliotti, F
Hoechst 33258是一种结合核酸的化合物。我们报告Hoechst 33258对卡氏肺孢子虫f.在卡氏肺孢子虫肺炎的小鼠模型中以及在体外对抗白色念珠菌和都柏林念珠菌。相对于生理盐水处理，小鼠接种卡氏肺孢子虫后每天给予37.5 mg Hoechst 33258/kg体重14天，通过PCR或银染色后显微镜检查检测到的卡氏肺孢子虫生物体数量减少约100倍。作为比较，基于15至20 mg甲氧苄啶-磺胺甲恶唑/kg剂量的甲氧苄啶组分的治疗使卡氏肺孢子虫的数量减少约四倍。在2或4 MM Mg 2+中观察到卡氏肺孢子虫I组内含子剪接的体外抑制，50%抑制浓度（IC 50）为30 μ M，表明RNA是可能的靶点。然而，Hoechst 33258抑制具有和不具有I组内含子的念珠菌菌株的生长。IC（50）的范围从1至9 μ M的菌株与组I内含子和12和32 μ M的两个菌株没有组I内含子。这些研究表明，结合真菌核酸的化合物有可能被开发为肺孢子虫和可能的其他真菌的新疗法，特别是如果它们可以针对哺乳动物细胞中不存在的结构，如自我剪接内含子。
Hoechst 33258 is a compound that binds nucleic acids. We report that Hoechst 33258 exhibits antimicrobial activity against Pneumocystis carinii f. sp. muris in a mouse model for P. carinii pneumonia and against Candida albicans and Candida dubliniensis in vitro. Relative to saline treatment, a 14-day, daily treatment of mice with 37.5 mg of Hoechst 33258/kg of body weight after inoculation with A carinii reduced by about 100-fold the number of P. carinii organisms detected by either PCR or by microscopy after silver staining. For comparison, treatment based on a dose of 15 to 20 mg of the trimethoprim component in trimethoprim-sulfamethoxazole/kg reduced the number of P. carinii by about fourfold. In vitro inhibition of P. carinii group I intron splicing was observed with a 50% inhibitory concentration (IC50)of 30 mu M in 2 or 4 MM Mg2+, suggesting RNA as a possible target. However, Hoechst 33258 inhibits growth of Candida strains with and without group I introns. IC(50)s ranged from 1 to 9 mu M for strains with group I introns and were 12 and 32 mu M for two strains without group I introns. These studies demonstrate that compounds that bind fungal nucleic acids have the potential to be developed as new therapeutics for Pneumocystis and possibly other fungi, especially if they could be directed to structures that are not present in mammalian cells, such as self-splicing introns.