Alligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis
Author:
Zhijie Yang, Yijun Qiao, Emil Strøbech, Jens Preben Morth, Grit Walther, Tue Sparholt Jørgensen, Kah Yean Lum, Gundela Peschel, Miriam A. Rosenbaum, Viola Previtali, Mads Hartvig Clausen, Marie Vestergaard Lukassen, Charlotte Held Gotfredsen, Oliver Kurzai, Tilmann Weber & Ling Ding
Date: 26 October 2024
Abstract:
Fungal infections pose a great threat to public health and there are only four main types of antifungal drugs, which are often limited with toxicity, drug-drug interactions and antibiotic resistance. Streptomyces is an important source of antibiotics, represented by the clinical drug amphotericin B. Here we report the discovery of alligamycin A (1) as an antifungal compound from the rapamycin-producer Streptomyces iranensis through genome-mining, genetics and natural product chemistry approaches. Alligamycin A harbors a unique chemical scaffold with 13 chiral centers, featuring a β-lactone moiety, a [6,6]-spiroketal ring, and an unreported 7-oxo-octylmalonyl-CoA extender unit incorporated by a potential crotonyl-CoA carboxylase/reductase. It is biosynthesized by a type I polyketide synthase which is confirmed through CRISPR-based gene editing. Alligamycin A displayed potent antifungal effects against numerous clinically relevant filamentous fungi, including resistant Aspergillus and Talaromyces species. β-Lactone ring is essential for the antifungal activity since alligamycin B (2) with disruption in the ring abolished the antifungal effect. Proteomics analysis revealed alligamycin A potentially disrupts the integrity of fungal cell walls and induces the expression of stress-response proteins in Aspergillus niger. Discovery of the potent antifungal candidate alligamycin A expands the limited antifungal chemical space.
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