Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp.
Background/Objectives: There is an urgent need for new and improved anthelmintics that are not constrained by existing resistance pathways and that can safeguard the health and welfare of animals. Methods: An integrated platform of chemical, bioassay, and cultivation profiling applied to a library o...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
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| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/13/12/1222 |
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| Summary: | Background/Objectives: There is an urgent need for new and improved anthelmintics that are not constrained by existing resistance pathways and that can safeguard the health and welfare of animals. Methods: An integrated platform of chemical, bioassay, and cultivation profiling applied to a library of microbes isolated from Australian livestock pasture soil was used to detect and guide the production, isolation, characterization, identification, and evaluation of new natural products with anthelmintic properties. Results: A global natural products social (GNPS) molecular network analysis of 110 Australian pasture-soil-derived microbial extracts prioritized for antiparasitic activity identified unique molecular families in the extract of <i>Streptomyces</i> sp. S4S-00185A06, a strain selectively active against <i>Dirofilaria immitis</i> microfilariae. UPLC-DAD analysis identified metabolites with unique UV-vis chromophores and unprecedented molecular formulas. A chemical investigation of <i>Streptomyces</i> sp. S4S-00185A06 yielded goondicones A–H (<b>1</b>–<b>8</b>) as new examples of a rare class of spiro-isoindolinones, with structures assigned on the basis of detailed spectroscopic analysis, ECD calculations, and biosynthetic considerations. Conclusions: While goondicones <b>1</b>–<b>8</b> exhibit little to no in vitro inhibitory activity against Gram-positive, Gram-negative, and/or fungal pathogens, human carcinoma cells, or the livestock gastrointestinal parasite <i>Haemonchus contortus</i> L1–L3 larvae, <b>5</b> and <b>6</b> (and, to a lesser extent, <b>1</b>) inhibit the motility of heartworm <i>Dirofilaria immitis</i> microfilaria (IC<sub>50</sub> 10–11 μM). A structure activity relationship analysis based on the co-metabolites <b>1</b>–<b>8</b> suggests that (i) an 8-OH is preferable to 8–oxo moiety, (ii) 20-NMe and 3-OH moieties are essential, and (iii) C-9 epimerization exerts no discernible impact on in vitro potency. |
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| ISSN: | 2079-6382 |