Biosynthetic Pathways and Regulation of Antibacterial Compounds From Endophytic Fungi: From Chemistry to Genomics and Biotechnology

Endophytic fungi are non-pathogenic symbionts that represent a rich source of structurally diverse bioactive secondary metabolites. However, genome-mining studies reveal that most of their biosynthetic gene clusters (BGCs) remain transcriptionally silent under standard laboratory conditions, leaving much of their chemical diversity unexplored. This review examines antibacterial natural products from endophytic fungi by integrating three complementary aspects: metabolite chemistry, biosynthetic pathways, and strategies for activating cryptic BGCs. Endophytic fungi produce polyketides, non-ribosomal peptides, terpenoids, phenylpropanoid-derived compounds, and hybrid metabolites with antibacterial activities mediated through inhibition of ribosomes, cell wall and membrane biosynthesis, and bacterial resistance mechanisms. Their genomes encode diverse PKS, NRPS, TPS, and hybrid biosynthetic systems, many of which remain cryptic. Advances in chemical elicitation, co-cultivation, epigenetic modulation, CRISPR-based engineering, genome mining, and machine learning are accelerating the activation of silent clusters and the assignment of BGCs to their metabolites. Several fungal metabolites exhibit potent activity against multidrug-resistant pathogens, including MRSA, and some enhance the efficacy of existing antibiotics. This review highlights current progress, identifies remaining challenges in metabolite production and BGC annotation, and outlines future directions for translating endophytic fungi into a sustainable platform for next-generation antibacterial drug discovery.