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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MDPI AG
2024-12-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/13/12/1222 |
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| author | Jianying Han David F. Bruhn Cynthia T. Childs Yovany Moreno Angela A. Salim Taizong Wu Robert J. Capon |
| author_facet | Jianying Han David F. Bruhn Cynthia T. Childs Yovany Moreno Angela A. Salim Taizong Wu Robert J. Capon |
| author_sort | Jianying Han |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2d3c5ef4d480415ab2807deed4bb5e7a |
| institution | DOAJ |
| issn | 2079-6382 |
| language | English |
| publishDate | 2024-12-01 |
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| series | Antibiotics |
| spelling | doaj-art-2d3c5ef4d480415ab2807deed4bb5e7a2025-08-20T02:55:53ZengMDPI AGAntibiotics2079-63822024-12-011312122210.3390/antibiotics13121222Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp.Jianying Han0David F. Bruhn1Cynthia T. Childs2Yovany Moreno3Angela A. Salim4Taizong Wu5Robert J. Capon6Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, AustraliaBoehringer Ingelheim Animal Health, USA Inc., 1730 Olympic Drive, Athens, GA 30601, USABoehringer Ingelheim Animal Health, USA Inc., 1730 Olympic Drive, Athens, GA 30601, USABoehringer Ingelheim Animal Health, USA Inc., 1730 Olympic Drive, Athens, GA 30601, USAInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, AustraliaKey Laboratory of Marine Genetic Resources, Third Institute of Oceanography, Ministry of Natural Resources, 184 Daxue Road, Xiamen 361005, ChinaInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, AustraliaBackground/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.https://www.mdpi.com/2079-6382/13/12/1222anthelminticcitizen science<i>Dirofilaria immitis</i>microbial natural productspiro-isoindolinoneSoils for Science |
| spellingShingle | Jianying Han David F. Bruhn Cynthia T. Childs Yovany Moreno Angela A. Salim Taizong Wu Robert J. Capon Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp. Antibiotics anthelmintic citizen science <i>Dirofilaria immitis</i> microbial natural product spiro-isoindolinone Soils for Science |
| title | Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp. |
| title_full | Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp. |
| title_fullStr | Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp. |
| title_full_unstemmed | Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp. |
| title_short | Goondicones A–H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived <i>Streptomyces</i> sp. |
| title_sort | goondicones a h spiro isoindolinone heartworm anthelmintics from an australian pasture soil derived i streptomyces i sp |
| topic | anthelmintic citizen science <i>Dirofilaria immitis</i> microbial natural product spiro-isoindolinone Soils for Science |
| url | https://www.mdpi.com/2079-6382/13/12/1222 |
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