Troponoids Can Inhibit Growth of the Human Fungal Pathogen Cryptococcus neoformans.
Cryptococcus neoformansis 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 againstC. neoformansWe screened 56 troponoids for their ability to inhibitC. neoformansgrowth 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.
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA donlinmj@slu.edu.|Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Maureen J
MJ
Donlin
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Anthony
A
Zunica
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Ashlyn
A
Lipnicky
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA.
Aswin K
AK
Garimallaprabhakaran
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA.|PhD Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, USA.
Alex J
AJ
Berkowitz
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA.
Alexandre
A
Grigoryan
Center for World Health and Medicine, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Marvin J
MJ
Meyers
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
John E
JE
Tavis
Department of Chemistry, Brooklyn College, The City University of New York, Brooklyn, New York, USA.|PhD Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, USA.
Ryan P
RP
Murelli
D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000254:growth & development; D015725:Fluconazole / Q000494:pharmacology; D006801:Humans; D008826:Microbial Sensitivity Tests; D014334:Tropolone / Q000494:pharmacology
D000935:Antifungal Agents; D014334:Tropolone; D000666:Amphotericin B; D015725:Fluconazole
Cryptococcus neoformans; antifungal agents; tropolones