Related Experiment Video
Updated: Mar 7, 2026
Assessing the Putative Anticryptococcal Properties of Crude and Clarified Extracts from Mollusks
Published on: December 2, 2022
Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans
Maureen J Donlin1,2, Anthony Zunica2, Ashlyn Lipnicky2
1Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA donlinmj@slu.edu.
Abstract:
Cryptococcus neoformans is a pathogen that is common in immunosuppressed patients. It can be treated with amphotericin B and fluconazole, but the mortality rate remains 15 to 30%. Thus, novel and more effective anticryptococcal therapies are needed. The troponoids are based on natural products isolated from western red cedar, and have a broad range of antimicrobial activities. Extracts of western red cedar inhibit the growth of several fungal species, but neither western red cedar extracts nor troponoid derivatives have been tested against C. neoformans We screened 56 troponoids for their ability to inhibit C. neoformans growth and to assess whether they may be attractive candidates for development into anticryptococcal drugs. We determined MICs at which the compounds inhibited 80% of cryptococcal growth relative to vehicle-treated controls and identified 12 compounds with MICs ranging from 0.2 to 15 μM. We screened compounds with MICs of ≤20 μM for cytotoxicity in liver hepatoma cells. Fifty percent cytotoxicity values (CC50s) ranged from 4 to >100 μM. The therapeutic indexes (TI, CC50/MIC) for most of the troponoids were fairly low, with most being <8. However, two compounds had TI values that were >8, including a tropone with a TI of >300. These tropones are fungicidal and are not antagonistic when used in combination with fluconazole or amphotericin B. Inhibition by these two tropones remains unchanged under conditions favoring cryptococcal capsule formation. These data support the hypothesis that troponoids may be a productive scaffold for the development of novel anticryptococcal therapies.
Insights
Novel troponoids show promise as new treatments for Cryptococcus neoformans infections, a common threat to immunosuppressed patients. These compounds exhibit potent antifungal activity and favorable safety profiles, offering a potential alternative to existing therapies.
Area of Science:
- Mycology
- Medicinal Chemistry
- Pharmacology
Background:
- Cryptococcus neoformans is a significant opportunistic pathogen, particularly in immunocompromised individuals.
- Current treatments like amphotericin B and fluconazole have limitations, with high mortality rates (15-30%) necessitating novel therapeutic strategies.
- Troponoids, derived from western red cedar, possess broad antimicrobial properties but their efficacy against C. neoformans was previously unevaluated.
Purpose of the Study:
- To screen a library of 56 troponoids for their inhibitory activity against Cryptococcus neoformans growth.
- To evaluate the cytotoxicity and therapeutic potential of promising troponoid candidates.
- To assess the fungicidal and synergistic properties of selected troponoids in combination with established antifungal drugs.
Main Methods:
- Minimum inhibitory concentrations (MICs) were determined for 56 troponoids against C. neoformans.
- Cytotoxicity was assessed in liver hepatoma cells to determine 50% cytotoxicity values (CC50).
- Therapeutic indexes (TI = CC50/MIC) were calculated, and combination studies with fluconazole and amphotericin B were performed.
Main Results:
- Twelve troponoids demonstrated significant inhibition of C. neoformans growth, with MICs ranging from 0.2 to 15 μM.
- Two troponoids exhibited high therapeutic indexes (TI > 8), with one tropone showing a TI > 300.
- These lead troponoids were fungicidal, did not antagonize fluconazole or amphotericin B, and maintained activity despite conditions promoting fungal capsule formation.
Conclusions:
- Troponoids represent a promising scaffold for developing novel anticryptococcal therapies.
- Specific troponoid compounds display potent activity, favorable safety profiles, and synergistic potential, addressing the unmet need for effective treatments against C. neoformans.
- Further investigation into troponoids could lead to new drug candidates to combat cryptococcosis.
