: Plant-endophyte associations represent an inexhaustible source of novel metabolites, exhibiting significance in environment, agriculture and pharmaceutical perspectives. The global outbreak of life threatening diseases necessitate a need for a more targeted approach through efficient drug-discovery programs. In recent times, endophytes as “bio-factories” have been extensively explored for the production of novel, bioactive metabolites demonstrating therapeutic properties. Resources in computational biology co-integrated with combinational chemistry have made significant contributions in this field, aiding in the discovery and screening of potential “drug-like” molecules from endophytes. The review provides a meta-analysis of bioactive metabolite production from endophytes, extensively discussing the bio-prospection of natural products for pharmaceutical applications. In light of the emerging importance of endophytes as anti-infective agents, an exploration of the pharmaceutical design of novel chemical entities and analogues has enabled efficient and cost-effective drug discovery programs. However, bottlenecks in endophyte biology and research require a better understanding of endophyte dynamics and mechanism of bioactive metabolite production towards a sustainable drug discovery program.

Withania somnifera owing to its strong and remarkable stress tolerance property is a reliable candidate for the determination of genes involved in mechanism of adaption/tolerance of various stress conditions. 187 AP2/ERF gene related transcripts (GRTs) were identified during comprehensive search in W. somnifera transcriptome repertoire. Major hits in homology search were observed from the model plant Arabidopsis and members of Solanaceae family. Cloning, expression analysis of the gene and genetic transient transformation with the gene (WsAP2) were performed to predict its functional role in planta. Enhanced expression of some of the pathway genes for terpenoid biosynthesis was observed in transformed tissues in comparison to the control tissues. It is speculated that WsAP2 gene crucially regulates the expression of GGPPS gene in addition to the regulation of other important genes of terpenoid pathway via induction of expression of other genes such as HMGR, CAS, DXS and DXR. To the best of our knowledge, this is the first report representing detailed study of AP2/ERF gene family in W. somnifera. It is also suggested from the study that gene might have role in eliciting responses to combat stress and attribute the strong stress tolerant property associated with the plant.

Transcription factors (TFs) are important regulators of cellular and metabolic functions including secondary metabolism. Deep and intensive RNA-seq analysis of Withania somnifera using transcriptomic databases provided 3532 annotated transcripts of transcription factors in leaf and root tissues, belonging to 90 different families with major abundance for WD-repeat (174 and 165 transcripts) and WRKY (93 and 80 transcripts) in root and leaf tissues respectively, followed by that of MYB, BHLH and AP2-ERF. Their detailed comparative analysis with Arabidopsis thaliana, Capsicum annum, Nicotiana tabacum and Solanum lycopersicum counterparts together gave interesting patterns. However, no homologs for WsWDR representatives, LWD1 and WUSCHEL, were observed in other Solanaceae species. The data extracted from the sequence read archives (SRA) in public domain databases were subjected to re-annotation, re-mining, re-analysis and validation for dominant occurrence of WRKY and WD-repeat (WDR) gene families. Expression of recombinant LWD1 and WUSCHEL proteins in homologous system led to enhancements in withanolide content indicating their regulatory role in planta in the biosynthesis. Contrasting expression profiles of WsLWD1 and WsWUSCHEL provided tissue-specific insights for their participation in the regulation of developmental processes. The in-depth analysis provided first full-spectrum and comparative characteristics of TF-transcripts across plant species, in the perspective of integrated tissue-specific regulation of metabolic processes including specialized metabolism.

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