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. 2024 Dec 17;13(12):1222.
doi: 10.3390/antibiotics13121222.

Goondicones A-H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived Streptomyces sp

Jianying Han  1 , David F Bruhn  2 , Cynthia T Childs  2 , Yovany Moreno  2 , Angela A Salim  1 , Taizong Wu  3 , Robert J Capon  1
Affiliations

Goondicones A-H: Spiro-Isoindolinone Heartworm Anthelmintics from an Australian Pasture-Soil-Derived Streptomyces sp

Jianying Han et al. Antibiotics (Basel). .

Abstract

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 Streptomyces sp. S4S-00185A06, a strain selectively active against Dirofilaria immitis microfilariae. UPLC-DAD analysis identified metabolites with unique UV-vis chromophores and unprecedented molecular formulas. A chemical investigation of Streptomyces sp. S4S-00185A06 yielded goondicones A-H (1-8) 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 1-8 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 Haemonchus contortus L1-L3 larvae, 5 and 6 (and, to a lesser extent, 1) inhibit the motility of heartworm Dirofilaria immitis microfilaria (IC50 10-11 μM). A structure activity relationship analysis based on the co-metabolites 1-8 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.

Keywords: Dirofilaria immitis; Soils for Science; Streptomyces; anthelmintic; citizen science; microbial natural product; spiro-isoindolinone.

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Conflict of interest statement

David Bruhn, Cynthia Childs, and Yovany Moreno are employees of Boehringer Ingelheim Animal Health, USA Inc. All remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Streptomyces sp. S4S-00185A06 metabolites, goondicones A–H (1–8).
Figure 2
Figure 2
Selected 2D NMR (DMSO-d6) correlations for 1–2 designating (A) common subunits A–C and connectivity and (B) a diagnostic ROESY correlation for 2 that defines relative configurations for 1 and 2.
Figure 3
Figure 3
(A) ECD spectra for (1), experimental (black), calculated 14R,9S (red dashed), and calculated 14S,9R (blue). (B) ECD spectra for (2), experimental (black), calculated 14R,9R (red dashed), and calculated 14S,9S (blue).
Figure 4
Figure 4
Selected 2D NMR (DMSO-d6) correlations for 3–4.
Figure 5
Figure 5
Selected 2D NMR (DMSO-d6) correlations for 5–8.
Figure 6
Figure 6
(A) ECD spectra for (5), experimental (black), calculated 14S,9S,8R (red dashed), and calculated 14S,9S,8S (blue). (B) ECD spectra for (6), experimental (black), calculated 14S,9R,8R (red dashed), and calculated 14S,9R,8S (blue).
Figure 7
Figure 7
Known spiro-isoindolinone natural products 9 and 10.
Figure 8
Figure 8
Plausible biosynthesis of spiro-isoindolinones 1–10.
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