Introduction
The yeast species Saccharomyces cerevisiae is a model eukaryotic organism that has been used by humans for centuries for brewing, baking, and winemaking, but in recent years, it has become a valuable tool for scientific discovery (Gaikani et al. 2024, Sattlegger and Schiemann 2026). In 1996, it was the first eukaryotic organism to have its entire genome sequenced, enabling the rapid development of genetic modification methods (Engel et al.
2013). These techniques have been replicated in other yeast species such as Pichia spp. and Candida spp., including the creation of gene knockout strains, incorporation of specific mutations, protein tagging, and heterologous expression (i.e. introducing genes from another organism to express their products in yeast) (Noble and Johnson 2005, Schwarzmüller et al. 2014, Wang et al.
2020). However, despite the value of these genetic tools, the use of yeast in natural product research is usually limited to measuring cytotoxicity or antifungal effects via growth inhibition assays.
Natural products represent a major source of bioactive molecules with important applications in medicine, and chemical investigation of species native to the Pacific region has been particularly fruitful, with the discovery of active compounds providing scientific insight into the mechanisms underlying their traditional use by Indigenous peoples. In 1975, a bacterial sample from the soil of Rapa Nui (Easter Island) yielded the natural product rapamycin, which was initially identified for its antifungal activity (Vézina et al. 1975).
Subsequent studies into its mechanism of action revealed potent immunosuppressive and antiproliferative properties, leading to its clinical use in organ transplantation and cancer treatment. Research into microorganisms and endemic species from the Pacific region continues to uncover novel compounds with important medical applications. While many investigations into natural products from the Pacific region have been screened against at least one species of yeast for antifungal activity (Supplementary Table S1), this review focuses on studies of natural products from Australia, Polynesia, Melanesia, Micronesia, New Zealand, Fiji, Samoa, Solomon Islands, Tonga, and Vanuatu (Fig.
1), with particular emphasis on yeast-based approaches to investigate their biological activity and mechanisms of action. A subset of these studies is discussed in more detail below.
Chemical genetic tools employing yeast
Despite the abundance of novel compounds isolated from Pacific organisms, further inquiry into their bioactivity is usually limited. In many cases, screening is limited to cytotoxic or antimicrobial assays in cancer cell lines or bacteria, respectively, with the mechanism of action behind any observed effects remaining unknown. Understanding the biological pathways targeted by a compound is crucial for drug discovery, as it informs both target specificity and potential toxicity.
Yeast provide a powerful system for investigating mechanisms of action and other cellular processes (Parsons et al. 2006, Hillenmeyer et al. 2008, Lee et al.
2014, Piotrowski et al. 2017), owing to their genetic tractability, amenability to manipulation, and rapid growth. In addition to their utility in mechanism of action studies, the ease with which yeast can be genetically engineered makes them an effective platform for a range of applications, such as the expression of heterologous proteins.
This versatility is exemplified by the production of recombinant vaccines, such as those for hepatitis B and human papillomavirus, in yeast (Ramos-Vega et al. 2025). The value of yeast as a model organism is underpinned by the conservation of many genes and cellular pathways with humans, enabling the identification of drug-relevant interactions; this differs from antifungal studies where yeast serve as the target organism.
Yeast-based genetic methods enable multiple complementary approaches for investigating cellular mechanisms. Yeast hybrid systems are widely used to study molecular interactions by fusing a protein of interest (“bait”) to the DNA-binding domain of a transcription factor, and a second interacting molecule (“prey”) to its activation domain (Fields and Song 1989). Interaction between bait and prey reconstitutes a functional transcription factor, leading to reporter gene expression that generates a measurable signal.
In yeast one-hybrid assays, protein–DNA interactions are detected, whereas yeast two-hybrid assays are used to study protein–protein interactions (Reece-Hoyes and Walhout 2012). Yeast three-hybrid systems use a third molecule that acts as a bridging ligand between bait and prey (Romo et al. 1998).
Tagging proteins with green fluorescent protein (GFP) enables visualization of gene expression and the localization of proteins by fluorescence microscopy (Fig. 2A). Gene deletion mutants enable the creation of strains with increased sensitivity to compounds, for example by disrupting efflux transport systems or removing key components of target pathways.
In combination with the ability of yeast to exist in multiple ploidy states, these approaches have enabled genome-wide chemical genetic screens.
HIP/HOP (haploinsufficiency profiling and homozygous profiling) assays are genome-wide chemical genetic screens that employ libraries of yeast deletion mutants, in which each strain lacks a different gene. By exposing these strains to a molecule with an unknown mechanism of action, the strains deficient in genes involved in the compound’s target pathway will exhibit altered sensitivity compared to wild-type strains. In HIP assays, heterozygous diploid strains carry a single copy deletion of a gene, whereas in HOP assays, both copies are deleted in homozygous strains (Fig.
3). As HIP strains express less of the target protein, a lower concentration of the compound of interest is required to inhibit it, resulting in increased sensitivity in these mutants when treated with a sub-lethal dose (Deutschbauer et al. 2005).
In contrast, HOP strains lack the gene product entirely, highlighting genes involved in compensatory or parallel pathways rather than the primary target; however, only non-essential genes may be removed completely. This approach provides a powerful method for identifying the molecular targets and pathways affected by bioactive compounds. Similar to HOP, haploid deletion screens employ yeast that do not express the gene product at all, as only a single copy of the gene is present and deleted; however, these screens are typically used to identify genes that influence sensitivity to a compound rather than directly infer the primary target.
Each strain may be labelled with unique DNA barcode sequences (UP and DN tags), located upstream and downstream of the deleted gene, to facilitate easy identification and quantification.
The application of yeast-based chemical genetic approaches, such as HIP/HOP screening, has enabled the systematic investigation of the mechanisms of action of natural products. The following sections present case studies of compounds isolated from Pacific organisms (Fig. 4), demonstrating how these methods have been used to identify molecular targets and biological pathways.
Chemical genetics to determine mechanism of action in natural products: case studies
Marine sponges
The New Zealand sponge Mycale hentscheli produces peloruside A (1, PelA), a bioactive compound that has been the subject of extensive study (West et al. 1999, Kanakkanthara et al. 2016).
Like the chemotherapeutic agent paclitaxel, PelA has potent microtubule-stabilizing activity and causes cell cycle arrest, inducing apoptosis (Hood et al. 2002). Wilmes et al.
(2012) performed HIP/HOP assays with PelA and diploid S. cerevisiae deletion mutant libraries to better understand PelA’s mechanism of action, including secondary targets and interactive networks. The 13 gene hits from HIP assays were unable to be validated individually and failed to identify the primary, known target of PelA, tubulin. HOP assays produced 12 validated gene hits, including five that were significant for both the UP and DN tags: RTS1, SAC1, MAD1, MAD2, and LSM1.
These genes are involved in the regulation of mitosis and the cell cycle, steroid biosynthesis, transport, protein synthesis, RNA processing, and secretion.
Other metabolites isolated from M. hentscheli have also been studied using yeast-based systems. Mycalamides have antiviral, cytotoxic, and immunosuppressive activities, and Venturi et al. (2012) tested mycalamide A (2) against haploid S. cerevisiae strains with deletions related to drug resistance, as this is an important aspect of potential therapeutics.
They found that mycalamide A behaves as a substrate for the efflux transporter Pdr5p, but this effect did not appear to be conserved in human cells, indicating mycalamides may have therapeutic value in cases of drug resistance. Pateamine A (3), also isolated from M. hentscheli (Northcote et al. 1991), was used to synthesize the bridging molecule for use in yeast three-hybrid assays.
By harnessing endogenous yeast enzymes, a ketone was reduced to a chiral alcohol, generating a compound capable of acting as a third molecule to facilitate interaction between bait and prey proteins (Romo et al. 1998).
In addition to Mycale hentscheli, other sponges have been investigated. Laulimalide (4) was simultaneously reported in 1988 by two research groups after isolation from the Vanuatuan sponge Spongia mycofijiensis (Quinoa et al. 1988) and the Indonesian sponge Hyattella sp., as well as the nudibranch (Chromodoris lochi) that was feeding on it (Corley et al.
1988). The compound was subsequently identified in sponge extracts from Japan, Fiji, and Tonga (Jefford et al. 1996, Tanaka et al.
1996, Cutignano et al. 2001, Johnson et al. 2007).
Being of the same compound class as PelA (i.e. marine sponge-derived macrolides), laulimalide is also a microtubule-stabilizing agent that binds to β-tubulin and interferes with cell division (Bennett et al. 2010). In a study investigating both laulimalide and PelA, isolated from the Tongan marine sponge Cacospongia mycofijiensis and the New Zealand marine sponge M. hentscheli, respectively, S. cerevisiae hemizygous deletion library screening indicated that both compounds inhibit microtubule depolymerization-dependent processes, especially the early pathway of spindle orientation and the end-on pulling-mediated separation of chromosomes (Best et al.
2013). This is consistent with the microtubule-stabilizing abilities of laulimalide and PelA and reveals potentially synergistic drug targets that could be used in combination therapies for the treatment of cancer. To validate the use of yeast as a model system to identify new anticancer drugs that interact with the laulimalide/PelA binding site, Hanna et al.
(2014) used site-directed mutagenesis to change single amino acids in the yeast laulimalide/PelA binding site, including mutations known to cause resistance in human ovarian cancer cells (e.g. A296T, R306H). Mutations A296T and R306H, as well as others, led to laulimalide/PelA resistance in yeast, and therefore, it was concluded that yeast is an appropriate model system to study binding and stabilization mechanisms of microtubules in mammalian cells.
Further studies on sponge-derived metabolites have identified additional bioactive compounds. The New Zealand marine sponge Hamigera tarangaensis was first reported to contain bromocyclooctane by Cambie et al. (1995).
Further investigation afforded hamigerans A–L, with hamigeran G (5) showing particular cytotoxicity to HL-60 promyelocytic leukaemic cells (Wellington et al. 2000, Singh et al. 2013).
To screen for genes involved in the mode of action of hamigeran G, S. cerevisiae homozygous diploid strains were used in HOP assays that identified genes related to the Golgi apparatus and Golgi vesicle transport, indicating that hamigeran G may target protein sorting and transport in the Golgi network (Singh et al. 2013). However, further studies on HEK293 cells found no significant effects on Golgi structure or function (Singh et al.
2019). Mitochondrial genes were also enriched in the genetic screen, but only minor effects were observed when hamigeran G was tested in HL-60 cells with mitochondrial gene knockouts. As the screen was based on homozygous deletions, the identified genes may reflect downstream or compensatory processes, suggesting that complementary approaches such as HIP may be required to identify the primary target.
Yeast-based approaches have also been applied to more complex mechanistic systems. Puupehenone (6, PUUP) was first isolated from Chondrosia chucalla sponges collected in Hawaii and the Marshall Islands by Ravi et al. (1979).
Subsequent studies on PUUP and related compounds from marine sponges from Hawaii, Indonesia, New Caledonia, the Bahamas, Australia, and the South China Sea demonstrated antifungal efficacy against S. cerevisiae, Candida albicans, and C. tropicalis (Kohmoto et al. 1987, Hamann and Scheuer 1991, Hamann et al. 1993, Urban and Capon 1996, Bourguet-Kondracki et al.
1999, Piña et al. 2003, Ciavatta et al. 2007).
PUUP exhibits synergistic activity with the echinocandin caspofungin, increasing its efficacy four-fold in resistant strains (Tripathi et al. 2020). Transcriptomic analysis of S. cerevisiae treated with PUUP and caspofungin either in combination or separately showed that genes associated with cell wall stress, the primary target of caspofungin, were not upregulated in the presence of PUUP alone, and mutants with constitutive expression of the cell wall integrity pathway showed suppression of this signalling when treated with PUUP.
HIP analysis revealed overlap between strains hypersensitive to PUUP and those hypersensitive to inhibitors of the heat shock protein Hsp90, prompting further investigation using yeast mutants designed to assess Hsp90 pathway activity. Molecular docking suggested that PUUP binds at the interface between heat shock protein Hsp90 and its co-chaperone Cdc37 involved in the cell division cycle. These findings indicate that PUUP may inhibit the formation of a Hsp90–Cdc37 complex, which is required for the activation of protein kinases crucial to the cell wall integrity pathway, thereby impairing signalling and enhancing sensitivity to caspofungin.
Other marine organisms
Beyond sponges, natural products from other marine organisms have also been investigated using yeast-based approaches. The sea cucumber Australostichopus mollis (formerly Stichopus mollis), found in New Zealand and Australia, produces neothyonidioside (7), a saponin that inhibits the growth of S. cerevisiae (Moraes et al. 2004, 2005).
HOP analysis highlighted genes associated with membrane homeostasis and membrane-dependent processes such as vesicular trafficking (Yibmantasiri et al. 2012). Although saponins are known to compromise membrane integrity, measurement of intracellular component leakage did not indicate membrane lysis.
Neothyonidioside-resistant strains of S. cerevisiae were therefore generated to further shed light on the mechanism of action. A synthetic gene array constructed using these strains identified NCP1, an essential gene involved in ergosterol biosynthesis, as the resistance locus. Resistant strains displayed reduced ergosterol content, suggesting that ergosterol may play a critical role in neothyonidioside activity.
Further analyses indicated that neothyonidioside binds ergosterol at the plasma membrane to form a saponin‒sterol complex that prevents multivesicular body vesicle formation. Thus, mutants with reduced ergosterol levels do not form this complex and exhibit resistance to neothyonidioside toxicity.
Screening of an aminol natural product, 3-epi-xestoaminol C (8) isolated from the New Zealand brown alga Xiphophora chondrophylla against a haploid deletion library of S. cerevisiae indicated that its mechanism of action is associated with lipid metabolism and cytoskeleton organization (Dasyam et al. 2014). As this compound is a deoxysphingolipid, a class of molecules known to disrupt actin dynamics, these findings are consistent with its expected biological activity and support the chemical genetic analysis.
To investigate the mechanism of action for pyocyanin (9), a natural product isolated from Pseudomonas aeruginosa sampled from the ocean floor in Hawaii, Angell et al. (2006) analyzed its effects using the Yeast S98 Array, which enables genome-wide quantification of mRNA expression across 6400 open reading frames. Some of the most significant changes were observed in genes associated with oxidative stress, and this was validated by performing RT-PCR (Muller 2002).
These findings confirm pyocyanin’s known mechanism of action as an inducer of oxidative damage.
Amantelide A (10), isolated from a marine cyanobacterium (Oscilliatoriales sp.) collected in Tumon Bay, Guam, was tested against knockout mutants of S. cerevisiae and Schizosaccharomyces pombe lacking genes encoding for ergosterol biosynthesis, as amantelides have structural similarities to other natural products that target the membrane and interact with ergosterol (Elsadek et al. 2021). The mutants retained sensitivity to amantelide A, suggesting an unspecific interaction with the ergosterol pathway.
HOP screening performed using a pdr1∆pdr3∆xxx∆ library of S. cerevisiae revealed the enrichment of hits lacking genes responsible for cell wall biogenesis and organization. Since membrane disruptors trigger the upregulation of cell wall biogenesis, this supported the hypothesis that amantelide A targets the cell membrane. Also, the overlapping results with nystatin indicated a similar mechanism of action to polyene antifungals, which bind directly to ergosterol (Carolus et al.
2020). Lipid-binding assays testing the binding of amantelide A to liposomes with and without incorporated sterols showed increased binding of amantelide A to lipid membranes in the presence of sterols, and haemolytic studies demonstrated membrane pore formation. HOP analysis had also identified enrichment of actin-related genes, and an actin polymerization assay demonstrated the stimulation of polymerization by amantelide A.
Together, these findings showed that amantelide A binds to ergosterol-containing membranes and then causes pore formation and, ultimately, cell death, with potential secondary interactions involving the actin cytoskeleton.
Echinochrome A (11, EchA) was isolated from shells and spines of New Zealand kina (sea urchins) and was inhibitory to the growth of S. cerevisiae (Hammond et al. 2024). A S. cerevisiae library of GFP-tagged mutants enabled visualization of proteins affected by the compound.
Genes associated with metal ion metabolism were implicated, and the corresponding proteins were localized to the mitochondria. Supplementation with iron rescued growth in treated cells, and a chrome azurol S assay showed that EchA chelates iron with efficiency comparable to ethylenediaminetetraacetic acid (EDTA), a known metal chelator. Screening of a haploid S. cerevisiae deletion library revealed enrichment of genes involved in oxidative stress response, and cells that were exposed to hydrogen peroxide showed improved survival when treated with EchA, indicating an antioxidant effect in yeast.
Fungi
Natural products derived from fungi represent another important source of bioactive compounds. A New Zealand Fusarium sp. produces the natural product tetramic acid-289 (12, TA-289), which exhibits cytotoxicity in S. cerevisiae (Quek et al. 2013).
HOP analysis yielded a coherent theme in the phenotypes of the S. cerevisiae deletion strains that were hypersensitive to TA-289: these strains demonstrated altered capacities for growth on non-fermentable carbon sources, sensitivity to oxidants, and abnormal mitochondrial morphology, suggesting that TA-289 perturbs mitochondrial function. TA-289-resistant mutants displayed cross-resistance to H2O2, which indicates that TA-289 causes oxidative stress, and it was confirmed that TA-289 increases the production of reactive oxygen species (ROS). However, strains lacking genes involved in the electron transport chain (ETC), a major source of ROS, did not show complete resistance to TA-289; resistance would be expected if TA-289 directly targets the ETC, resulting in the production of ROS.
Furthermore, ROS levels did not increase in the ETC deletion strains after exposure to TA-289, and it was concluded that an intact ETC is required for ROS generation by TA-289. However, analyses with a mitochondrial GFP fusion protein revealed that the ETC deletion strains still had abnormal mitochondrial morphology, and therefore, the altered morphology was not a result of increased ROS levels. Instead, it was proposed that the induction of apoptosis, caused by TA-289 directly inhibiting a mitochondrially localized target(s), was responsible for the abnormal mitochondrial morphology and ROS generation.
A strain of Epicoccum nigrum, isolated as an airborne contaminant in a University of Auckland laboratory, produced the natural product disalt of epipyrone A (13, DEA), which inhibits the growth of S. cerevisiae and C. albicans (Lee et al. 2020). Chemical genetic screening with a S. cerevisiae haploid deletion library identified the elo2∆ deletion strain as the most sensitive to DEA.
ELO2 encodes a fatty acid elongase involved in sphingolipid biosynthesis. Metabolomic analysis revealed significant differences in intracellular and extracellular metabolite abundance between the elo2∆ mutant and its parental strain in the presence of DEA. It was inferred that DEA likely affects cell membrane permeability and the elo2∆ strain is less resilient due to reduced levels of sphingolipids and longer-chain fatty acids in the cell membrane (Lee et al.
2024). Subsequent fluorescence microscopy with a GFP-tagged S. cerevisiae library revealed changes in the abundance or localisation of several proteins in DEA-treated cells (Fig. 2B), including Csg2 and Sur1, which are involved in sphingolipid biosynthesis.
These findings provide additional evidence that the proposed primary mode of action of DEA involves the disruption of sphingolipid/fatty acid biosynthesis.
An alternative approach was undertaken by Boot et al. (2007), who used bioassay-guided fractionation of a marine-derived strain of Aspergillus fumigatus, isolated from sediment off the coast of Vanuatu, to obtain 11-O-methylpseurotin A (14). Crude extracts were tested against 16 haploid S. cerevisiae strains with deletions in genes involved in cytokinesis and cell cycle control.
The hof1∆ strain exhibited the greatest inhibition relative to wild-type, guiding the isolation of 11-O-methylpseurotin A. As Hof1 functions in cytokinesis, compounds that selectively inhibit the hof1Δ strain are likely to target pathways parallel to Hof1 function; accordingly, Boot et al. proposed that 11-O-methylpseurotin A may be useful for probing cell cycle–related pathways with potential relevance to cancer.
Plants
Plant-derived natural products provide further examples of compounds with bioactivity that can be explored using yeast-based approaches. In Samoan traditional medicine, the fresh leaf juice from the tree Psychotria insularum, locally called matalafi, is used to treat inflammation associated with a wide range of ailments (Molimau-Samasoni et al. 2021).
HIP analysis of the leaf homogenates, prepared with a traditional healer, enriched for 23 genes, nine of which are conserved in humans and associated with iron or zinc metabolism. GFP/RFP-tagged yeast strains showed that the expression of iron transporters increased in the presence of the leaf homogenate, indicating a state of iron deficiency. Measurement of intracellular iron levels showed a decrease in iron, and a chrome azurol S assay confirmed iron chelation.
Bioactivity-guided fractionation of the plant extract, using yeast growth rescue with supplemental iron, enabled isolation of the flavonol glycosides rutin and nicotiflorin. Murine splenocytes treated with the plant homogenate or rutin showed reduced production of proinflammatory cytokines and increased production of anti-inflammatory cytokines, which is consistent with the traditional use of matalafi.
Extracts from Acca sellowiana (Feijoa), a plant native to South America but commonly grown as an agricultural product in New Zealand, have also been investigated for antifungal activity. Metabolite profiling identified compounds correlated with antifungal activity against S. cerevisiae and several Candida species, with HIP analysis implicating chitin synthesis pathways (Mokhtari et al. 2018).
Subsequent studies on extracted tannin polyphenols identified the ethanol adduct of vescalagin (15) as having the highest bioactivity against S. cerevisiae, and therefore, it was chosen for further investigation of its mechanism of action (Mokhtari et al. 2024). HOP analysis with a S. cerevisiae deletion mutant library identified retromer recycling, mitochondrial function, and iron and zinc homeostasis as potential mediatory mechanisms in EtOH-vescalagin bioactivity, and GFP-tagged yeast libraries revealed the increased expression of iron and zinc transporters following treatment.
Chrome azurol S assays and intracellular measurements of iron confirmed that EtOH-vescalagin acts as an iron chelator, reducing intracellular iron levels and, thus, stimulating the uptake of iron in a compensatory response. In contrast, EtOH-vescalagin increased intracellular zinc levels, and fluorescent staining of zincosomes showed an increase in their abundance. These results suggest disruption of metal homeostasis is a key component of the mechanism of action of EtOH-vescalagin.
In a study by Blockley-Powell et al. (2025), the steam extract (SE) from the leaves of another New Zealand plant, kānuka (Kunzea robusta), demonstrated synergistic activity with rapamycin, and genome-wide mutant libraries of S. cerevisiae were used to determine the key genes and pathways responsible for this synergism. High doses of rapamycin yield unfavourable side effects, and a combinatorial approach could increase the therapeutic effect while reducing the dose and side effects.
Kānuka has been used in traditional medicine by the indigenous Māori people of New Zealand and has shown antiviral, antibacterial, antifungal, anti-Phytophthora, and anti-inflammatory activities (Bloor 1992, Tomblin et al. 2014, Chen et al. 2016, Lawrence et al.
2019). Therefore, kānuka SE and rapamycin were tested for synergistic activity in a yeast growth inhibition assay. Once found to have a synergistic effect, they were screened against the 4300 strains in the haploid S. cerevisiae pdr1Δpdr3ΔxxxΔ library.
Ninety-nine strains had confirmed sensitivity to the combined treatment, and almost half of those strains were also sensitive to higher concentrations of rapamycin, indicating that kānuka SE either increases the bioavailability of rapamycin or works through the same or a similar pathway. Network analysis of genetic interactors illustrated the enrichment of gene clusters in known rapamycin-targeted processes, further supporting the deduction that kānuka SE increases the bioavailability of rapamycin. Visualization of yeast cells transformed with methionine transport protein Mup1-GFP and exposed to the combined treatment showed an increase in the number of sorting vacuoles for Mup1-GFP during endocytosis, a phenotype comparable to that observed during starvation.
Bioassay-guided fractionation via yeast growth inhibition assays yielded nerolidol (16) as a strongly synergistic component in kānuka SE.
Other yeast technology and future directions
In addition to chemical genetic approaches, yeast have been employed in a range of complementary techniques relevant to natural product research. Heterologous expression systems have enabled the functional production of gene products from Pacific organisms, as demonstrated by Walsh et al. (1998), who successfully expressed the xynA gene encoding a xylanase enzyme from a Thermotoga sp. isolated in Fiji in Kluyveromyces lactis.
Yeast-based disease models have also been developed to assess bioactivity, with Sinane et al. (2024) utilizing an ERG6 deletion strain expressing prion-like proteins to screen sponge extracts from French Polynesia for anti-prion activity. Stevenson et al.
(2021) transformed a biosynthetic gene cluster encoding the polyketide aureolic acid, a scaffold for anticancer agents, from a New Zealand soil metagenome library into S. cerevisiae for recombination and reconstitution.
Protein–protein interaction systems such as the yeast two-hybrid assay have further expanded the utility of yeast, including studies investigating the pathogenic mechanisms of kiwifruit-associated microbes and the enzymatic processes underlying plastic degradation in marine fungi (Dharmaraj et al. 2019, Zhang et al. 2022).
Together, this work demonstrates the versatility of yeast-based systems for investigating complex biological processes beyond conventional chemical genetic screening.
The studies presented in this review demonstrate that yeast-based approaches provide detailed insight into the mechanisms of action of natural products derived from Pacific organisms. Across numerous compound classes and source organisms, yeast-based chemical genetic screening, protein interaction assays, and functional genomics have enabled the identification of molecular targets, affected pathways, and broader cellular responses.
Ethical considerations are also critical when studying natural products derived from Pacific organisms, and research involving biological materials from Indigenous lands should be conducted in collaboration with Indigenous communities, recognizing their roles as knowledge holders and guardians of these resources. Frameworks for benefit sharing and intellectual property must be incorporated to ensure equitable outcomes and respect for knowledge systems, as emphasized by Garba et al. (2023).
Historical examples, such as the discovery of rapamycin from soil samples collected on Rapa Nui (Easter Island), further highlight the ethical complexities surrounding bioprospecting, Indigenous rights, and the lack of downstream benefit sharing despite major scientific and commercial success (Powers and Kellogg 2022). In some Pacific regions, these principles are formalized through agreements such as the Nagoya Protocol, which prioritizes fair and equitable access and benefit sharing, while in New Zealand, WAI262 further highlights the importance of appropriate governance and partnership (Leal et al. 2020, Golan et al.
2022, Clark et al. 2024). Chemical genetic approaches that elucidate mechanisms of action can, in some cases, provide scientific insight into the basis of traditional uses of natural products, reinforcing the value of integrating Indigenous knowledge with modern biomedical research.
As shown throughout this review, yeast-based chemical genetics and complementary approaches can provide critical insight into the mechanism of action of bioactive compounds. Incorporating yeast-based methodologies more routinely into natural product research workflows has the potential to substantially enhance the biological characterization of newly discovered compounds. Future studies should integrate chemical genetic screening, interaction-based assays, and functional genomics to more comprehensively define the biological activity of natural products.
Supplementary Material