Identification of fungal natural products with potent inhibition in Toxoplasma gondii .

Autor: Jiang T; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, USA., Godinez-Macias KP; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, USA., Collins JE; Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA., Lee JW; College of Pharmacy, Duksung Women's University, Seoul, Republic of Korea., Wendt KL; Natural Products Discovery Group, Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA., Carolino K; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, USA., Chakrabarti D; Division of Molecular Microbiology, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA., Cichewicz RH; Natural Products Discovery Group, Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA., Winzeler EA; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Jazyk: angličtina
Zdroj: Microbiology spectrum [Microbiol Spectr] 2024 Apr 02; Vol. 12 (4), pp. e0414223. Date of Electronic Publication: 2024 Feb 29.
DOI: 10.1128/spectrum.04142-23
Abstrakt: In an effort to identify novel compounds with potent inhibition against Toxoplasma gondii, a phenotypic screen was performed utilizing a library of 683 pure compounds derived primarily from terrestrial and marine fungi. An initial screen with a fixed concentration of 5 µM yielded 91 hits with inhibition comparable to an equal concentration of artemisinin. These compounds were then triaged based on known biological and chemical concerns and liabilities. From these, 49 prioritized compounds were tested in a dose response format with T. gondii and human foreskin fibroblasts (HFFs) for cytotoxicity. Ten compounds were identified with an IC 50 less than 150 nM and a selectivity index (SI) greater than 100. An additional eight compounds demonstrated submicromolar IC 50 and SI values equal to or greater than 35. While the majority of these scaffolds have been previously implicated against apicomplexan parasites, their activities in T. gondii were largely unknown. Herein, we report the T. gondii activity of these compounds with chemotypes including xanthoquinodins, peptaibols, heptelidic acid analogs, and fumagillin analogs, with multiple compounds demonstrating exceptional potency in T. gondii and limited toxicity to HFFs at the highest concentrations tested.
Importance: Current therapeutics for treating toxoplasmosis remain insufficient, demonstrating high cytotoxicity, poor bioavailability, limited efficacy, and drug resistance. Additional research is needed to develop novel compounds with high efficacy and low cytotoxicity. The success of artemisinin and other natural products in treating malaria highlights the potential of natural products as anti-protozoan therapeutics. However, the exploration of natural products in T. gondii drug discovery has been less comprehensive, leaving untapped potential. By leveraging the resources available for the malaria drug discovery campaign, we conducted a phenotypic screen utilizing a set of natural products previously screened against Plasmodium falciparum . Our study revealed 18 compounds with high potency and low cytotoxicity in T. gondii , including four novel scaffolds with no previously reported activity in T. gondii . These new scaffolds may serve as starting points for the development of toxoplasmosis therapeutics but could also serve as tool compounds for target identification studies using chemogenomic approach.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
Externí odkaz: