Salomon, C. E. | bioRxiv Science

bioRxiv2025

Norditerpene natural products from subterranean fungi with anti-parasitic activity

Cryptosporidium is a common, waterborne gastrointestinal parasite that causes diarrheal disease worldwide. Currently there are no effective therapeutics to treat cryptosporidiosis in at-risk populations. Since natural products are a known source of anti-parasitic compounds, we screened a library of extracts and pure natural product compounds isolated from bacteria and fungi collected from subterranean environments for activity against Cryptosporidium parvum. Eight structurally related norditerpene lactones isolated from the fungus Oidiodendron truncatum collected from the Soudan Iron mine in Minnesota showed potent activity and were further tested to identify the most active compounds. The availability of a diverse suite of natural structural analogs with varying activities allowed us to determine some structure activity relationships for both anti-parasitic activity as well as cytotoxicity. The two most potent compounds, oidiolactones A and B, had EC50s against intracellular Cryptosporidium parvum of 530 and 240 nM respectively without cytotoxicity to confluent HCT-8 host cells. Both compounds also inhibited the related parasite Toxoplasma gondii. Oidiolactone A was active against asexual, but not sexual, stages of C. parvum, and killed 80% of the parasites within 8 hours of treatment. This compound reduced C. parvum infection by 70% in IFN{gamma}-/- mice, with no signs of toxicity. The high potency, low cytotoxicity, and in vivo activity combined with high production, easy isolation from fungi, and synthetic accessibility make oidiolactones A and B attractive scaffolds for the development of new anti-Cryptosporidium therapeutics.

microbiology↗

bioRxiv2021

Synthesis and Evaluation of Acridone and Xanthone Epoxides with Anti-MRSA and Anti-MSSA Activity

A series of acridone and xanthone-based compounds bearing 1,2-epoxypropyl or 1,2-propanediol substituents were synthesized and evaluated for activity against MRSA and MSSA bacterial strains. The results indicate a correlation exists between the number of epoxide groups and activity, with peak MIC values observed for bis-epoxy derivatives. Both activity and heathy cell toxicity was shown to decrease with the addition of a third epoxy group. The corresponding ring-opened diol analogs were devoid of activity, demonstrating the critical function of the epoxide in mediating antimicrobial activity. The most active compounds were also screened using a regulated antisense RNA expression library. The results show no increase in activity against cells sensitized by down-regulation of the most common drug targets, including DNA gyrase, DNA topoisomerase, tRNA synthetase, and the fatty acid biosynthesis pathway. The compounds are postulated to function as membrane disrupting agents, similar to the xanthone natural product -mangostin.

microbiology↗