Biosynthetic Gene Clusters in Polyene Antibiotic Production

Polyene antibiotics are a class of macrocyclic polyketides distinguished by a conjugated series of double bonds and a polar sugar residue, most commonly mycosamine. These compounds, synthesised by soil-dwelling actinomycetes, exhibit potent antifungal activity through selective binding to ergosterol in fungal membranes. The genes responsible for their assembly are organised into contiguous biosynthetic gene clusters (BGCs) that typically encode modular polyketide synthases (PKSs), tailoring enzymes such as cytochrome P450 monooxygenases and glycosyltransferases, pathway-specific regulatory proteins, and self-resistance factors. The modular nature of PKSs permits the stepwise condensation of simple acetate and propionate building blocks to form the polyene backbone, after which dedicated enzymes introduce hydroxylations, epoxidations and glycosylations that define the compound’s solubility, stability and toxicity profile. Regulatory genes within BGCs fine-tune expression in response to developmental cues and environmental signals, while transporters and resistance proteins protect the producer organism. Advances in genome mining and synthetic biology have accelerated the discovery of silent or cryptic clusters, enabling heterologous expression and rational pathway engineering for yield improvement and the generation of novel analogues with enhanced therapeutic indices.

Research from Nature Portfolio

Recent studies have isolated a novel Streptomyces strain from agricultural soil that produces lucensomycin, a polyene macrolide with broad-spectrum antifungal efficacy. Genome mining of this strain revealed a BGC with high homology to known polyene clusters, incorporating modular PKS genes alongside cytochrome P450 and glycosyltransferase modules. Genetic confirmation of the cluster was achieved through targeted disruption, which abolished antifungal activity, and complementation restored production. Bioassays demonstrated potent inhibition of key phytopathogenic fungi, highlighting the potential of this BGC for the development of eco-friendly fungicides and the value of in-field screening combined with genome analysis for novel BGC discovery.

Biosynthetic Gene Clusters in Polyene Antibiotic Production publication trend

The graph below shows the total number of articles in biosynthetic gene clusters in polyene antibiotic production across all publications each year (not limited to Nature Index journals).

Technical terms

Biosynthetic Gene Cluster (BGC): A contiguous set of genes encoding enzymes, regulators and transporters for secondary metabolite assembly.

Polyketide Synthase (PKS): A modular enzyme complex that catalyses the sequential condensation of acyl units into polyketide chains.

Glycosyltransferase: An enzyme that attaches sugar moieties to aglycone cores, influencing solubility and target specificity.

Cytochrome P450 Monooxygenase: An oxidising enzyme that introduces hydroxyl or epoxide functionalities into polyketide backbones.

Heterologous Expression: The transfer and functional expression of a gene or gene cluster in a non-native host organism.

Mycosamine: An aminated sugar residue commonly attached to polyene macrolides, critical for membrane targeting and antifungal activity.

References

1. Isolation of Streptomyces inhibiting multiple-phytopathogenic fungi and characterization of lucensomycin biosynthetic gene cluster. Scientific Reports (2024).
2. Identification of RimR2 as a positive pathway-specific regulator of rimocidin biosynthesis in Streptomyces rimosus M527. Microbial Cell Factories (2023).
3. The Identification and Heterologous Expression of the Biosynthetic Gene Cluster Encoding the Antibiotic and Anticancer Agent Marinomycin. Biomolecules (2024).
4. New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining. Antibiotics (2022).