Exploring the modern approaches to enhance fungal endophyte-derived bioactive secondary metabolites

Over the past few decades, microbial-derived bioactive compounds have been tested for antiviral, antimicrobial, and anticancer properties. In addition, fungal-derived bioactive secondary metabolites (SMs) are increasingly being suggested as suitable alternative sources of potent bioactive compounds. The development of suitable, precise in vitro and in vivo screening techniques may contribute to identifying the biochemical and physiological effects of compounds. This advancement in bioassay evaluation techniques helps identify potential bioactive microbes rapidly. The main obstacles, however, have been the production of insufficient amounts of chemicals, endophytes' attenuation or loss of ability to produce the molecule of interest when grown in cultures, and fungal endophytes' failure to exhibit their full biosynthetic potential in lab conditions. These have led to the use of small chemical elicitors that activate the silent biosynthetic gene clusters (BGCs) in fungi, causing epigenetic alterations that increase the amount of desired metabolites or trigger the synthesis of hitherto unknown compounds. The silent BGCs were activated to maximize production of bioactive secondary metabolites, thereby increasing the yield of desired compounds or triggering the synthesis of novel metabolites. Other strategies include gene knocking, inducing mutations, heterologous expression, one strain-many compounds (OSMAC), epigenetic modifications, etc. This review is focused on the mechanism of plant-microbe interaction in enhancing the biosynthesis of fungal metabolites along with the BGCs for the biosynthesis of the bioactive fungal metabolites. Furthermore, we also discuss the genomic mining approaches for BGCs, the role of ribosomal engineering, precursor feeding, and various elicitors to explore the structural diversity of novel bioactive compounds.