Spirolactone, an unprecedented antifungal β-lactone spiroketal macrolide from Streptomyces iranensis

Yang, Z.; Qiao, Y.; Strobech, E.; Morth, J. P.; Walther, G.; Jorgensen, T. S.; Peschel, G.; Rosenbaum, M. A.; Previtali, V.; Clausen, M. H.; Lukassen, M. V.; Gotfredsen, C. H.; Kurzai, O.; Ding, L.

doi:10.1101/2024.04.17.589928

bioRxiv · 10.1101/2024.04.17.589928

Spirolactone, an unprecedented antifungal β-lactone spiroketal macrolide from Streptomyces iranensis

Yang, Z.·Qiao, Y.·Strobech, E.·Morth, J. P.·Walther, G.·Jorgensen, T. S.·Peschel, G.·Rosenbaum, M. A.·Previtali, V.·Clausen, M. H.·Lukassen, M. V.·Gotfredsen, C. H.·Kurzai, O.·Ding, L.

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Abstract

Fungal infections pose a great threat to public health and there are limited antifungal medicaments. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. The rapamycin-producer Streptomyces iranensis harbors an unparalleled Type I polyketide synthase, which codes for a novel antifungal macrolide alligamycin A (1), the structure of which was confirmed by NMR, MS, and X-ray crystallography. Alligamycin A harbors an undescribed carbon skeleton with 13 chiral centers, featuring a ({beta}-lactone moiety, a [6,6]-spiroketal ring, and an unprecedented 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential novel crotonyl-CoA carboxylase/reductase. The ali biosynthetic gene cluster was confirmed through CRISPR-based gene editing. Alligamycin A displayed profound antifungal effects against numerous clinically relevant filamentous fungi, including Talaromyces and Aspergillus species. ({beta}-Lactone ring is essential for the antifungal activity and alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupted the integrity of fungal cell walls and induced the expression of stress-response proteins in Aspergillus niger. Alligamycins represent a new class of potential drug candidate to combat fungal infections.

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Yang, Z., Qiao, Y., Strobech, E., Morth, J. P., Walther, G., Jorgensen, T. S., Peschel, G., Rosenbaum, M. A., Previtali, V., Clausen, M. H., Lukassen, M. V., Gotfredsen, C. H., Kurzai, O., Ding, L.. 2024-04-17. Spirolactone, an unprecedented antifungal β-lactone spiroketal macrolide from Streptomyces iranensis. https://doi.org/10.1101/2024.04.17.589928

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