A comprehensive review on bacterial endophytic secondary metabolites: a road map from crude extract to lead molecule production.

Endophytes are microorganisms that are concealed within the intracellular spaces of the plants in diverse ecological niches across varied habitats, are a prolific source of bioactive metabolites capable of inhibiting human pathogens responsible for mild to severe infections. The rising threat of antimicrobial resistance largely due to the indiscriminate use of antibiotics, has prompted the World Health Organization to advocate for rigorous stewardship of existing drugs while simultaneously urging the development of novel therapeutic alternatives. Several studies have reported emphasizing the application of multiple metabolites from endophytes however, exploring the mechanisms involved in the inhibition by a single effective metabolite which could help in unwinding the complexity during lead molecule synthesis. This review aims to present a comprehensive and strategic roadmap integrating upstream processes encompassing isolation, screening, and fermentation, with downstream methodologies for metabolite extraction, purification and structural elucidation, along with toxicity assessments for effective pharmaceutical applications. Furthermore, the discussion also considers the integration of predictive AI-ML models in accelerating the drug developmental pipeline for circumventing the traditional discovery bottlenecks highlighting the relevance to industrial translation and underlines the potential of endophyte-derived metabolites to target pathogenicity islands, offering a paradigm shift from bacterial eradication to anti-virulence strategies along with a focus on errors and limitations of endophytic research.