Alligamycin A, an antifungal β-lactone spiroketal macrolide from Streptomyces iranensis
Zhijie Yang1, Yijun Qiao1, Emil Strøbech1
1Department of Biotechnology and Biomedicine, Technical University of Denmark, Lyngby, Denmark.
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.
Insights
Researchers discovered alligamycin A, a novel antifungal compound from Streptomyces iranensis, effective against resistant fungi. This finding expands therapeutic options beyond existing antifungal drugs, addressing a critical public health need.
Area of Science:
- Microbiology
- Natural Product Chemistry
- Genomics
Background:
- Fungal infections present a significant global health challenge.
- Current antifungal therapies are limited by toxicity, drug interactions, and resistance.
- Streptomyces species are a proven source of clinically relevant antibiotics.
Purpose of the Study:
- To discover novel antifungal compounds from Streptomyces iranensis.
- To characterize the chemical structure and biosynthetic pathway of a new antifungal agent.
- To evaluate the antifungal efficacy and mechanism of action of the discovered compound.
Main Methods:
- Genome mining and bioinformatics analysis to identify biosynthetic gene clusters.
- Genetic manipulation using CRISPR-Cas9 to confirm the polyketide synthase pathway.
- Isolation, purification, and structural elucidation of the antifungal compound using natural product chemistry techniques.
- Antifungal susceptibility testing against clinically relevant fungal pathogens.
- Proteomics analysis to investigate the mechanism of action.
Main Results:
- Discovery and characterization of alligamycin A, a novel antifungal compound with a unique chemical scaffold including a β-lactone moiety and a [6,6]-spiroketal ring.
- Confirmation of biosynthesis via a type I polyketide synthase using CRISPR-based gene editing.
- Alligamycin A demonstrated potent antifungal activity against diverse filamentous fungi, including drug-resistant Aspergillus and Talaromyces species.
- The β-lactone ring was identified as crucial for antifungal activity.
- Proteomics data suggests alligamycin A disrupts fungal cell wall integrity and induces stress responses in Aspergillus niger.
Conclusions:
- Alligamycin A is a potent new antifungal agent with a unique structure, offering a promising candidate to combat resistant fungal infections.
- The discovery highlights the value of genome mining in identifying novel bioactive natural products.
- Alligamycin A expands the limited chemical space for antifungal drug development, addressing a critical unmet medical need.
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