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

Abstract

AbstractFungal infections pose a great threat to public health and there are limited antifungal medicaments.Streptomycesis an important source of antibiotics, represented by the clinical drug amphotericin B. The rapamycin-producerStreptomyces iranensisharbors 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. Thealibiosynthetic gene cluster was confirmed through CRISPR-based gene editing. Alligamycin A displayed profound antifungal effects against numerous clinically relevant filamentous fungi, includingTalaromycesandAspergillusspecies. (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 inAspergillus niger. Alligamycins represent a new class of potential drug candidate to combat fungal infections.