Systematic Exploration of Cryptic Biosynthetic Gene Clusters in Endophytic Fungi Associated with Rare Bioactive Plants: Genomic Insights and Prospects for Novel Metabolite Discovery

Abstract

Endophytic fungi residing in plants with distinct medicinal and chemical properties are increasingly considered as sources of gene clusters (BGCs) where genome encoding is largely unexpressed. This review analyses new genomic data on cryptic BGCs and the means to locate them and connect predicted pathways and metabolites. Studies on literature published from 2020 to 2025 were reviewed and checked against databases (Publisher, PubMed, Crossref, etc.) provided by scholars. Selected primary studies highlighted the presence of BGCs in Calcarisporium, Fusarium, Alternaria, Dactylonectria, Helotiales, Talaromyces, Diaporthe, Pyrenochaeta and several endophytes. A number of antiSMASH surveys showed substantial diversity in PKS, NRPS, and terpene and hybrid pathways. Several surveys of RNA and metabolomics continued to show a gap between genome and metabolome. In addition to conventional means like OSMAC, epigenetic perturbations, engineering of transcription factors and heterologous expression can be used to access recalcitrant metabolites. Since directly comparable study-level activation proportions were not found within verified literature, another statistical study with a Random-effects model was performed. It showed a pooled proportion of 0.347 (95% CI 0.272–0.429; I²=69.0%). Genome mining, metabolomics and functional activation, are the most defensible methods to go from the prediction of cryptic BGCs to the discovery of new metabolites.