Current Approaches and Implications in Discovery of Novel Bioactive Products from Microbial Sources.

Bioactive Natural Products (BNPs) are in high demand due to their disease-preventive capabilities and resistance to pathogens. However, our understanding of BNP-producing microbes is limited, because many microbial populations remain uncultivated. Various approaches have been employed to explore the potential of these hidden microbes for new bioactive therapeutic compounds. Nevertheless, the possibility of discovering BNPs from microbial communities is largely cryptic due to their unculturable nature and the absence of triggers to activate the dormant Biosynthetic Gene Clusters (BGCs). Metagenome sequencing, followed by mining and characterization, is an effective approach for discovering new therapeutic BNPs. The inactive state of BGCs can be activated through the combinatorial interaction of different microbial communities within a common niche, overcoming programmable co-evolutionary stress and producing new BNPs. The present review discusses and explores the potential of hidden, uncultivated microbes for discovering novel Bioactive Natural Products (BNPs). Moreover, it provides insights into optimizing microbial production systems and fostering sustainable drug discovery and development practices by integrating multidisciplinary strategies. This review also emphasizes the critical role of microbial sources in the ongoing search for new bioactive products that can meet the demands of modern healthcare and environmental sustainability.