Alligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
26 Oct 2024
26 Oct 2024
Historique:
received:
29
04
2024
accepted:
18
10
2024
medline:
27
10
2024
pubmed:
27
10
2024
entrez:
27
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39461983
doi: 10.1038/s41467-024-53695-3
pii: 10.1038/s41467-024-53695-3
doi:
Substances chimiques
Antifungal Agents
0
Macrolides
0
Lactones
0
Polyketide Synthases
79956-01-7
Spiro Compounds
0
spiroketal
0
Furans
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9259Subventions
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF23OC0082881
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF19OC0055818
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF19OC0055818
Organisme : Novo Nordisk Fonden (Novo Nordisk Foundation)
ID : NNF20CC0035580
Organisme : Innovationsfonden (Innovation Fund Denmark)
ID : Grant 3141-00013A
Informations de copyright
© 2024. The Author(s).
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