Abstract

Bacterial natural products have long been the foundation for many therapeutic agents. However, traditional culture-based approaches to discovering these products have been deprioritised by pharmaceutical companies, primarily due to the high rates of rediscovery. To revitalise the pipeline of new drugs, especially antibiotics-an area where natural products have historically played a crucial role-new technologies are essential. Culture-independent, or metagenomic, techniques combined with long-read sequencing technologies are now enabling the identification of novel biosynthetic gene clusters (BGCs). When paired with the heterologous expression of DNA extracted directly from environmental samples (eDNA), these approaches may provide access to untapped microbial biosynthetic diversity. This review explores industrial screening for new compounds and examines how modern technologies such as metagenomics, in situ cultivation, and pico-droplet-based screening are advancing the search for novel natural products. These approaches have the potential to greatly expand the discovery of new bioactive compounds, helping to address the growing need for new therapeutic agents.