Yeast chemical genetics to investigate mechanism of action of Pacific natural products.

Natural products are a major source of bioactive molecules with important applications in medicine, and investigation of species native to the Pacific region has been particularly fruitful, including species used in traditional and Indigenous medicinal practices. Yeast represents a powerful model system for investigating mechanisms of action and other cellular processes; however, their use in natural product research is often limited to growth inhibition or cytotoxicity assays, with underlying mechanisms remaining unclear. This review summarises studies on 17 natural products derived from Pacific organisms, including fungi, plants, and marine organisms, and highlights the application of yeast-based chemical genetic approaches, such as haploinsufficiency and homozygous profiling (HIP/HOP) and gene deletion screens, to investigate their mechanisms of action. These case studies demonstrate how such methods enable the identification of molecular targets and affected pathways, providing insight into the molecular basis of Pacific natural products and, in the context of traditional medicine, complementing Indigenous knowledge with mechanistic understanding. Greater integration of yeast-based methodologies into natural product research will enhance the biological characterisation of newly discovered compounds.