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Antimicrobial Agents and Chemotherapy, April 2005, p. 1326-1330, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1326-1330.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activity of Hoechst 33258 against Pneumocystis carinii f. sp. muris, Candida albicans, and Candida dubliniensis

Department of Chemistry,¹ Center for Human Genetics and Molecular Pediatric Disease,² Department of Pediatrics,³ Department of Microbiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York⁴

Received 29 September 2004/ Returned for modification 22 October 2004/ Accepted 22 December 2004

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 P. 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 µM 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. IC₅₀s ranged from 1 to 9 µM for strains with group I introns and were 12 and 32 µM 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.