The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis

Alqaisi, A.Q.I.; Mbekeani, A.J.; Bassas Llorens, M.; Elhammer, A.P.; Denny, P.W.

Abstract

Toxoplasma gondii is an obligate intracellular protozoan parasite of the phylum Apicomplexa, and toxoplasmosis is an important disease of both humans and economically important animals. With a limited array of drugs available there is a need to identify new therapeutic compounds. Aureobasidin A (AbA) is an antifungal that targets the essential inositol phosphorylceramide (IPC, sphingolipid) synthase in pathogenic fungi. This natural cyclic depsipeptide also inhibits Toxoplasma proliforation, with the protozoan IPC synthase orthologue proposed as the target. The data presented here show that neither AbA nor an analogue (Compound 20), target the protozoan IPC synthase orthologue or total parasite sphingolipid synthesis. However, further analyses confirm that AbA exhibits significant activity against the proliferative tachyzoite form of Toxoplasma, and Compound 20, whilst effective, has reduced efficacy. This difference was more evident on analyses of the direct effect of these compounds against isolated Toxoplasma, indicating that AbA is rapidly microbicidal. Importantly, the possibility of targeting the encysted, bradyzoite, form of the parasite with AbA and Compound 20 was demonstrated, indicating that this class of compounds may provide the basis for the first effective treatment for chronic toxoplasmosis.

Citation

Alqaisi, A., Mbekeani, A., Bassas Llorens, M., Elhammer, A., & Denny, P. (2018). The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis. Parasitology, 145(2), 148-155. https://doi.org/10.1017/s0031182017000506

• Journal Article Type: Article
• Acceptance Date: Mar 23, 2017
• Online Publication Date: May 10, 2017
• Publication Date: Feb 1, 2018
• Deposit Date: Mar 16, 2017
• Publicly Available Date: May 15, 2017
• Journal: Parasitology
• Print ISSN: 0031-1820
• Electronic ISSN: 1469-8161
• Publisher: Cambridge University Press
• Peer Reviewed: Peer Reviewed
• Volume: 145
• Issue: 2
• Pages: 148-155
• DOI: https://doi.org/10.1017/s0031182017000506
• Public URL: https://durham-repository.worktribe.com/output/1362045