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

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 (β-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. (β-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.