Cryptococcus neoformans is an opportunistic human fungal pathogen that is capable of causing life-threatening infections. These infections generally occur in individuals with compromised immunity such as those living with AIDS or those receiving immunosuppressive therapies to prevent organ rejection. There are approximately 1 million new cases of cryptococcosis every year, and over 650,000 deaths are attributed to it annually. The current therapeutic options are extremely limited and leave much to be desired.
This situation has resulted in significant interest in improving existing therapies and developing new ones. One approach to addressing this growing need that has recently garnered significant attention is screening compound libraries of pre-approved drugs for novel activities. An important advantage of this method is that the toxicological and pharmacological profiles for these compounds are already established, allowing for accelerated translation to clinical use.
We chose to screen the Prestwick library, a collection of 1200 off-patent, FDA-approved compounds, for activity against C. neoformans using an assay that specifically detects cell lysis to identify potential new antifungal. Of the 1200 compounds tested, 31 met our criteria for hits. Of these 31 compounds 14 exhibit characteristics that make them extremely attractive as new anticryptococcal agents. While we are in the process of investigating the potential of several of these compounds, this project focused on in-depth characterization of the antifungal activity and mode of action the triphenylethylene compounds. These compounds are estrogen receptor antagonists used in the treatment of estrogen receptor positive breast cancer, although they also have activity against other malignancies, indicating that there are additional targets.
Here we show that two clinically used triphenylethylenes, tamoxifen and toremifene, exhibit in vitro fungicidal activity at concentrations similar to established serum levels, are active in two important niches of cryptococcosis, the phagolysosome and the brain, and improve the efficacy of fluconazole, the most common treatment, in an experimental model of cryptococcosis. We have also identified two direct molecular targets in C. neoformans which will enable future rational optimization efforts. Although additional studies are warranted, this class of compounds has significant potential for improving the prognosis of those afflicted with cryptococcosis.
|Commitee:||Haidaris, Constantine, Miller, Benjamin L., Nilsson, Bradley L., Weix, Danial J.|
|School:||University of Rochester|
|Department:||School of Arts and Sciences|
|School Location:||United States -- New York|
|Source:||DAI-B 75/08(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Molecular chemistry, Organic chemistry|
|Keywords:||Antifungal, Cryptococcus, Drug discovery, Mode of action, Repurposing|
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