Field Of Natural Product Research Research Articles

Advancements and Challenges in Chemoinformatics: From Drug Discovery to Natural Products Research

Chemoinformatics, an interdisciplinary field combining chemistry, computer science, and information technology, is revolutionising scientific research by using computational methods to analyse, interpret, and predict chemical and biological data. This review explores its pivotal role across drug discovery and natural product research, highlighting key methodologies and challenges. It is critical in drug discovery because it expedites the identification and optimization of drug candidates through techniques such as virtual screening, molecular docking, and quantitative structure-activity relationship (QSAR) studies. It also facilitates the integration of computational chemistry with experimental validation, improving predictions iteratively. Chemoinformatics helps with managing databases, virtually screening bioactive compounds, and figuring out structures through molecular dynamics simulations and metabolomics in the field of natural products research. These tools enable researchers to explore the therapeutic potential of indigenous medicinal plants and other natural sources, facilitating the discovery of novel bioactive molecules with potential pharmaceutical applications. However, challenges such as data quality, computational resources, and ethical considerations persist, particularly in regions with limited infrastructure and expertise. The integration of machine learning and big data analytics promises to further enhance predictive modelling and accelerate discoveries in chemoinformatics. Keywords: Chemoinformatics, Drug Discovery, Natural Products, Research

Antimicrobial Metabolites from the Freshwater Fungus Tubeufia longihelicospora Strain GZCC 23-0405

In this study, five metabolites were successfully isolated from the culture medium of Tubeufia longihelicospora strain GZCC 23-0405, comprising two dimeric naphtha-γ-pyrones (1–2), two dimeric coumarins (3–4), and one alkaloid (5). The elucidation of their chemical structures relied on a combination of NMR, MS, and optical rotation methods. Interestingly, these compounds represent the first instances of such metabolites being isolated from helicosporous hyphomycetes. Additionally, compounds (1) and (2) exhibited significant antimicrobial potential, with MIC and MBC values of 62.0 μg mL-1 and 248 μg mL-1, respectively, against Pseudomonas aeruginosa. This study provides a comprehensive account of the extraction, isolation, structural characterization, and antimicrobial properties of these compounds, shedding light on their potential significance in the field of natural product research.

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES.

In the field of natural product research, the rediscovery of already-known compounds is one of the significant issues hindering new drug development. Recently, an innovative approach called bioactivity-HiTES has been developed to overcome this limitation, and several new bioactive metabolites have been successfully characterized by this method. In this study, we applied bioactivity-HiTES to Corynebacterium matruchotii, the human oral bacterium, with 3120 clinical drugs as potential elicitors. As a result, we identified two cryptic metabolites, methylindole-3-acetate (MIAA) and indole-3-acetic acid (IAA), elicited by imidafenacin, a urinary antispasmodic drug approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). MIAA showed weak antibacterial activity against a pulmonary disease-causing Mycobacterium conceptionense with an IC50 value of 185.7 μM. Unexpectedly, we also found that C. matruchotii metabolized fludarabine phosphate, a USFDA-approved anticancer drug, to 2-fluoroadenine which displayed moderate antibacterial activity against both Bacillus subtilis and Escherichia coli, with IC50 values of 8.9 and 20.1 μM, respectively. Finally, acelarin, a prodrug of the anticancer drug gemcitabine, was found to exhibit unreported antibacterial activity against B. subtilis with an IC50 value of 33.6 μM through the bioactivity-HiTES method as well. These results indicate that bioactivity-HiTES can also be applied to discover biotransformed products in addition to finding cryptic metabolites in microbes.

Production of high molecular-ordered stilbene oligomers for the study of their biological activity: total synthesis, bio-catalyzed synthesis and production by plant systems.

Though the iconic stilbene resveratrol and its related dimers constitute a top storyline in the field of natural product research, resveratrol oligomers (condensation >2) have been left aside despite their higher biological activity compared to that of the monomers. This situation largely results from the difficulty of getting them in sufficient quantities to enable evaluation of their biological properties in vivo. We present here a synthetic and critical analysis of the methods used for the production of high molecular-ordered stilbene oligomers of potential biomedical interest, gathering the most salient data regarding the approaches employed to prepare them by total synthesis, use of biomimetic approaches or through plant systems.

Preparation and Application of Molecularly Imprinted Polymers for Flavonoids: Review and Perspective

The separation and detection of flavonoids from various natural products have attracted increasing attention in the field of natural product research and development. Depending on the high specificity of molecularly imprinted polymers (MIPs), MIPs are proposed as efficient adsorbents for the selective extraction and separation of flavonoids from complex samples. At present, a comprehensive review article to summarize the separation and purification of flavonoids using molecular imprinting, and the employment of MIP-based sensors for the detection of flavonoids is still lacking. Here, we reviewed the general preparation methods of MIPs towards flavonoids, including bulk polymerization, precipitation polymerization, surface imprinting and emulsion polymerization. Additionally, a variety of applications of MIPs towards flavonoids are summarized, such as the different forms of MIP-based solid phase extraction (SPE) for the separation of flavonoids, and the MIP-based sensors for the detection of flavonoids. Finally, we discussed the advantages and disadvantages of the current synthetic methods for preparing MIPs of flavonoids and prospected the approaches for detecting flavonoids in the future. The purpose of this review is to provide helpful suggestions for the novel preparation methods of MIPs for the extraction of flavonoids and emerging applications of MIPs for the detection of flavonoids from natural products and biological samples.

Computational Literature-based Discovery for Natural Products Research: Current State and Future Prospects.

Literature-based discovery (LBD) mines existing literature in order to generate new hypotheses by finding links between previously disconnected pieces of knowledge. Although automated LBD systems are becoming widespread and indispensable in a wide variety of knowledge domains, little has been done to introduce LBD to the field of natural products research. Despite growing knowledge in the natural product domain, most of the accumulated information is found in detached data pools. LBD can facilitate better contextualization and exploitation of this wealth of data, for example by formulating new hypotheses for natural product research, especially in the context of drug discovery and development. Moreover, automated LBD systems promise to accelerate the currently tedious and expensive process of lead identification, optimization, and development. Focusing on natural product research, we briefly reflect the development of automated LBD and summarize its methods and principal data sources. In a thorough review of published use cases of LBD in the biomedical domain, we highlight the immense potential of this data mining approach for natural product research, especially in context with drug discovery or repurposing, mode of action, as well as drug or substance interactions. Most of the 91 natural product-related discoveries in our sample of reported use cases of LBD were addressed at a computer science audience. Therefore, it is the wider goal of this review to introduce automated LBD to researchers who work with natural products and to facilitate the dialogue between this community and the developers of automated LBD systems.

A Cross-Sectional Analysis of Knowledge, Beliefs and Practices Regarding Traditional Medicine Use among Pharmacy Students of Different Private and Government Universities of Lahore, Pakistan

Background: Students’ understanding regarding traditional medicine is a part of pharmacy curriculum. In Pakistan, be it students or healthcare professionals, little is known about the general importance of traditional medicine. Objectives: The aim of this study is to assess the students, enrolled in Doctor of Pharmacy Program, regarding their beliefs, knowledge and practices for use of medicinal plants. Methodology: The questionnaires were distributed among the Doctor of Pharmacy (Pharm-D) students. The data was analyzed using SPSS software (IBM, version. 22) and different statistical tests were applied, including descriptive analysis, t-test and Pearson chi squared test. Results: Total 254 responses were obtained in the study. While the outcome indicates that the majority of the participants (n=237: 93.3%) acknowledge the usefulness of traditional medicine. 151 (59.4%) participants believed that the traditional medicine is safe but 103 (40.6%) concerned about the side effects of herbal remedies. 187 (73.6%) reported the use of some type of medicinal plants in their life. Easy availability of traditional medicine was reported by 186 (73.2%) participants and 176 (69.3%) claimed the medicinal plants as inexpensive alternatives. The physician was kept informed about the concomitant administration of herbal with allopathic medicine in only 43 (16.9%). Stomach pain (14.17%) was most common sickness for which participants utilized traditional treatment, followed by cough (12.6%) and flu (10.63%). Mint (10.24%) was found to be the most commonly used medicinal plant, followed by aloe (9.84%) and ginger (7.48%). Conclusion: Detailed studies are still required to evaluate not only the students but also health care professionals about their understanding, prescribing practice and dealing with patients already using medicinal plants. This will help in improved management of the disorders and may lead further advancement in the field of natural product research and cutting off ill effects of allopathic treatment. Bangladesh Journal of Medical Science Vol. 21 No. 02 April’22 Page : 323-334

Development of a Critical Appraisal Tool (AIMRDA) for the Peer-Review of Studies Assessing the Anticancer Activity of Natural Products: A Step towards Reproducibility.

The journal of APJCP (Asian Pacific Journal of Cancer Prevention) focuses to gather relevant and up-to-date novel information’s related to cancer sciences. The research methodologies and approaches adopted by the researcher are prone to variation which may be desirable in the context of novel scientific findings however, the reproducibility for these studies needs to be unified and assured. The reproducibility issues are highly concerned when preclinical studies are reported in cancer, for natural products in particular. The natural products and medicinal plants are prone to a wide variation in terms of phytochemistry and phyto-pharmacology, ultimately affecting the end results for cancer studies. Hence the need for specific guidelines to adopt a best-practice in cancer research are utmost essential. The current AIMRDA guidelines aims to develop a consensus-based tool in order to enhance the quality and assure the reproducibility of studies reporting natural products in cancer prevention. A core working committee of the experts developed an initial draft for the guidelines where more focus was kept for the inclusion of specific items not covered in previous published tools. The initial draft was peer-reviewed, experts-views provided, and improved by a scientific committee comprising of field research experts, editorial experts of different journals, and academics working in different organization worldwide. The feedback from continuous online meetings, mail communications, and webinars resulted a final draft in the shape of a checklist tool, covering the best practices related to the field of natural products research in cancer prevention and treatment. It is mandatory for the authors to read and follow the AIMRDA tool, and be aware of the good-practices to be followed in cancer research prior to any submission to APJCP. Though the tool is developed based on experts in the field, it needs to be further updated and validated in practice via implementation in the field.

Liquid–Liquid Chromatography: Current Design Approaches and Future Pathways

Since its first appearance in the 1960s, solid support-free liquid-liquid chromatography has played an ever-growing role in the field of natural products research. The use of the two phases of a liquid biphasic system, the mobile and stationary phases, renders the technique highly versatile and adaptable to a wide spectrum of target molecules, from hydrophobic to highly polar small molecules to proteins. Generally considered a niche technique used only for small-scale preparative separations, liquid-liquid chromatography currently lags far behind conventional liquid-solid chromatography and liquid-liquid extraction in process modeling and industrial acceptance. This review aims to expose a broader audience to this high-potential separation technique by presenting the wide variety of available operating modes and solvent systems as well as structured, model-based design approaches. Topics currently offering opportunities for further investigation are also addressed.

Mammillaria Species-Polyphenols Studies and Anti-Cancer, Anti-Oxidant, and Anti-Bacterial Activities.

Discovering new natural resources of polyphenols is the aim of many recent studies in the field of natural product research. This study tentatively investigated the polyphenols profile of the stems of seven Mammillaria species (M. rhodantha, M. spinosissima, M. hahniana, M. crucigera, M. candida, M. albilanata, and M. muehlenpfordtii) using high performance liquid chromatography with DAD detector (HPLC-DAD) method. Furthermore, the anti-cancer, anti-oxidant, and anti-bacterial potentials of these extracts as well as major identified phenols were explored. The HPLC-DAD study confirmed the availability of six phenolic acids, including gentisic acid, chlorogenic acid, caffeic acid, protocatechuic acid, sinapic acid, and p-hydroxybenzoic acid. The dominant compounds were: gentisic acid in M. rhodantha and M. spinosissima; chlorogenic acid in M. muehlenpfordtii, M. crucigera, and M. rhodantha; and caffeic acid in M. rhodantha, M. crucigera, and M. spinosissima. Stems of Mammillaria sp. showed antiproliferative effects against HeLa, MCF-7, and Jurkat cells. In HeLa and MCF-7 cells, the best antiproliferative activities were found in the treatments with M. rhodantha, M. spinosissima, and M. muehlenpfordtii. The apoptotic assay of M. rhodantha, M. spinosissima, and M. muehlenpfordtii showed accumulation of necrotic cells in the early and late apoptotic phase. M. rhodantha, M. spinosissima, and M. muehlenpfordtii showed the highest anti-oxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), β-carotene bleaching, and ferric reducing anti-oxidant power (FRAP) assays. M. rhodantha was the best source of antioxidants. Mammillaria sp. showed moderate anti-bacterial effects against bacteria and the highest effects were found using the extracts of M. rhodantha, M. spinosissima, M. crucigera and M. muehlenpfordtii against most bacteria. The anti-bacterial activities were attributed to other phenolic compounds (e.g., chlorogenic acid) than gentisic acid, which was not active against most bacteria. Mammillaria sp. could be considered to be an important natural source of phenolic acids with anti-cancer, anti-bacterial, and anti-oxidant activities.

Application of response surface methodology as mathematical and statistical tools in natural product research

Response Surface Methodology (RSM) models combined with experimental designs were became popular in the recent years. Their advantages to analyze the interactive effects among different factors and the efficiency considerations encouraged more researchers to conduct natural product research employed with these models. A review about basic principles of factorial designs, central composite designs, Box-Behnken designs, and Doehlert designs which utilized along with the RSM and their applications in natural product research is presented. The objective of this review was to report various experimental design techniques and their applications in the field of natural product research. Furthermore, the characteristic of each designs are also presented and the trends of RSM applications in natural product research are also discussed in this paper.

Synergistic Effects of Curcumin and Piperine as Potent Acetylcholine and Amyloidogenic Inhibitors With Significant Neuroprotective Activity in SH-SY5Y Cells via Computational Molecular Modeling and in vitro Assay.

Hallmarks of Alzheimer’s disease (AD) pathology include acetylcholine (ACh) deficiency and plaque deposition. Emerging studies suggest that acetylcholinesterase (AChE) may interact with amyloid β (Aβ) to promote aggregation of insoluble Aβ plaques in brains of patients. Current therapeutic options available for AD patients, such as AChE inhibitors, provide only symptomatic relief. In this study, we screened four natural compounds believed to harbor cognitive benefits—curcumin, piperine, bacoside A, and chebulinic acid. In the first section, preliminary screening through computational molecular docking simulations gauged the suitability of the compounds as novel AChE inhibitors. From here, only compounds that met the in silico selection criteria were selected for the second section through in vitro investigations, including AChE enzyme inhibition assay, 3-(4,5-dimenthylthiazol-2-yl)-2,5-dimethyltetrazolium bromide (MTT) assay, Thioflavin T (ThT) assay, and biochemical analysis via a neuronal cell line model. Of the four compounds screened, only curcumin (−9.6 kcal/mol) and piperine (−10.5 kcal/mol) showed favorable binding affinities and interactions towards AChE and were hence selected. In vitro AChE inhibition demonstrated that combination of curcumin and piperine showed greater AChE inhibition with an IC50 of 62.81 ± 0.01 μg/ml as compared to individual compounds, i.e., IC50 of curcumin at 134.5 ± 0.06 μg/ml and IC50 of piperine at 76.6 ± 0.08 μg/ml. In the SH-SY5Y cell model, this combination preserved cell viability up to 85%, indicating that the compounds protect against Aβ-induced neuronal damage (p < 0.01). Interestingly, our results also showed that curcumin and piperine achieved a synergistic effect at 35 μM with an synergism quotient (SQ) value of 1.824. Synergistic behavior indicates that the combination of these two compounds at lower concentrations may provide a better outcome than singularly used for Aβ proteins. Combined curcumin and piperine managed to inhibit aggregation (reduced ThT intensity at 0.432 a.u.; p < 0.01) as well as disaggregation (reduced ThT intensity at 0.532 a.u.; p < 0.01) of fibrillar Aβ42. Furthermore, combined curcumin and piperine reversed the Aβ-induced up-regulation of neuronal oxidative stress (p < 0.01). In conclusion, curcumin and piperine demonstrated promising neuroprotective effects, whereas bacoside A and chebulinic acid may not be suitable lead compounds. These results are hoped to advance the field of natural products research as potentially therapeutic and curative AD agents.

Importance of ethnopharmacological studies in drug discovery: role of medicinal plants

Ethnopharmacology can be basically defined as “the interdisciplinary scientific exploration of the biologically active agents that are traditionally employed”. Therefore, the ethnopharmacological approach is based on a body of work that spans several disciplines such as botany, chemistry, and pharmacology. This includes field observations, descriptions of the utilization and bioactivities of folk remedies, botanical identification of the plant material as well as phytochemical and pharmacological research. Investigations of the indigenous remedies and their possible effects have attracted attention of many researchers for ages. Drug discovery from natural sources in the light of ethnopharmacological studies has an important role in the development of current therapeutic systems. Plants, animals and minerals are among the natural products that have been the basis in the treatment of many diseases for centuries. Recently, much attention has been paid to pharmacognostical, phytochemical and pharmacological studies of traditional medicinal plants. Moreover, biological activity potential of natural medicines has been investigated in many preclinical and clinical studies, revealing diverse biological effects of a wide range of plant derived compounds in various classes of chemical groups. The majority of the natural sources whose active compounds are currently employed actually has an ethnomedical use. Therefore, recently, many of the pharmaceutical companies have renewed their strategies in the field of natural product research in order to bring out potential sources and new molecules for the drug development. For the discovery and development of novel, safe and affordable medicines, the ethnopharmacological knowledge could be beneficial thanks to its approach that could be supported by experimental base. In the present study, ethnopharmacological aspects of herbal medicine and plant-based drug discovery process will be emphasized and important issues in their use as complementary medicine will be mentioned.

Larvicidal and Adult Mosquito Vector Attractant Activity of Tremella fuciformis Berk Mushroom Extract on Aedes aegypti (L.) and Culex sitiens Wiedemann (Diptera: Culicidae)

Chemical Constituents, Larvicidal Effects and Radical Scavenging Activity of Tetracera breyniana Schltdl. (Dilleniaceae)Cinthia C. de Lima, Rosangela P. Lyra Lemos, Lucia M. Conserva

Current strategies to induce secondary metabolites from microbial biosynthetic cryptic gene clusters

The genome of actinomycetes and several other microorganisms are endowed with many cryptic gene clusters that can code for previously undetected, a plethora of complex secondary metabolites. Under standard laboratory controlled conditions, the genes regulating these biosynthetic clusters are expressed at very low levels or remain phenotypically cryptic (silent). Over the past several decades, multi-drug-resistant bacteria have been observed with increased frequency, posing a significant threat to human health worldwide. The present alarming situation urgently calls for concerted global efforts for the discovery of new antimicrobials. The present situation, if not controlled, will take us again to the pre-antibiotic era. Today, in the post-genomic era, various new strategies such as the activation of cryptic gene clusters in microorganisms rejuvenate a new conviction in the field of natural product research that may lead to the identification of yet-unidentified novel secondary metabolites of therapeutic and other use. Decryptification of this versatile endogenous genetic reservoir may provide in the near future the more concrete rationale for antibiotic discovery. The present review is an attempt to provide a comprehensive detail, outlining current strategies that have been shown successful to activate cryptic biosynthetic gene clusters in microorganisms.

A fluorescence-based bioassay for antibacterials and its application in screening natural product extracts.

The reliable assessment of the biological activity of a minor component embedded in a complex matrix of several hundred compounds is a difficult but common task in the search for natural product-based antibiotics, for example, by bioassay-guided fractionation. To quantify the antibiotic properties, it is necessary to assess the cell viability. Direct measurements use CFU counts, OD measurements or detection via fluorescent or reducible dyes. However, natural extracts often already possess intrinsic dye, fluorescent, reducing or protein denaturing properties, or they contain insoluble compounds or general protein-binding (tanning) polyphenols as disturbing features, while at the same time very little of the selective antibiotic sought after is present. A promising alternative is provided by intrinsically produced bright fluorescent proteins. In this paper, a rapid, robust and concentration-dependent assay for screening antibiotics with genetically modified mutants of Bacillus subtilis 168 (PabrB-iyfp) is presented. The Gram-positive bacteria exhibit a native fluorescence during their exponential growth phase due to the expression of improved yellow fluorescent protein. To demonstrate the applicability in the field of natural product research, several compounds and extracts were screened for antibacterial activity, with an emphasis on those from the fungal genus Hygrophorus (waxy caps).

Tagging polyketides/non-ribosomal peptides with a clickable functionality and applications.

Bioorthogonal chemistry has recently emerged to be one of the most powerful tools in drug discovery and chemical biology. The exploration of it has successfully advanced the field of natural product research. In this Perspective, we survey current strategies for the installation of chemical handles into the molecular scaffolds of several major classes of natural products, including polyketides (PKs), non-ribosomal peptides (NRPs), and their hybrids. By tagging these natural products with chemical handles and coupling them with subsequent bioorthogonal reactions, researchers have visualized and studied the mode of action of natural products, as well as synthesized derivatives with better pharmaceutical properties. We conclude this Perspective by considering two questions: is there a general way to synthesize tagged PKs/NRPs? Does natural product labeling have a broader impact in the field of natural product research beyond current known applications?

Hepaptoprotective Activity of Aqueous Extract of Digitalis purpurea in Carbon Tetra Chloride Induced Hepatotoxicity in Albino Rats

Liver is a vital organ play a major role in metabolism and excretion of xenobiotics from the body. Liver injury or liver dysfunction is a major health problem that challenges not only health care professionals but also the pharmaceutical industry and drug regulatory agencies. Liver cell injury caused by various toxic chemicals (certain anti-biotic, chemotherapeutic agents, carbon tetrachloride (CCL4), thioacetamide (TAA) etc.), excessive alcohol consumption and microbes is well studied. Herbal medicines have been used in the treatment of liver diseases for a long time. A number of herbal preparations are available in the market. The present review is aimed at compiling data on promising phytochemicals from medicinal plants that have been tested in hepatotoxicity models using modern scientific system. A large number of populations suffer due to various reasons from hepatic diseases of unknown origin. The development of antihepatotoxic drugs being a major thrust area has drawn the attention of workers in the field of natural product research because synthetic drugs may cause serious side effects. The present research was aimed to study the in vivo hepatoprotective activity of methanolic extract of Digitali Purpurea L. in CCl4 induced hepatotoxicity in albino rats. The level of serum aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), alkaline phosphatase (ALP) and total bilirubin (T. BILI.) were determined to assay hepatotoxicity. CCl4 administration caused severe hepatic damage in rats as evidenced by elevated serum SGOT, SGPT, ALP and T. BILI. Levels. The extract of Digitalis Purpurea L. and silymarin administration prevented the toxic effect of CCl4 on the above serum parameters in both preventive and curative models. The present study concludes that, methanolic extract of Digitalis Purpurea L has significant hepatoprotective activity against CCl4 induced hepatotoxicity, which support folkloric utilization and further confirmed by the histological investigation. The observed activity may be associated with its high bioactive compounds including Purpurea glycoside –A, Digitoxin (a), Glucoodoroside–H, Gitoxin, Odoroside – H, Verodoxin, Digitalin, β-sitosterol, Cholesterol, Campesterol, Apigenin.

Access to High Value Natural and Unnatural Products through Hyphenating Chemical Synthesis and Biosynthesis

Access to natural products and their analogues is crucial. Such compounds have, for many years, played a central role in the area of drug discovery as well as in providing tools for chemical biology­. The ability to quickly and inexpensively acquire genome sequences has accelerated the field of natural product research. Access to genomic data coupled with new technologies for the engineering of organisms is resulting in the identification of large numbers of previously undiscovered natural products as well as an increased understanding of how the biosynthetic pathways responsible for the biogenesis of these compounds may be manipulated. This short review summarizes and reflects upon approaches to accessing natural products and has a particular focus on approaches combining molecular biology and synthetic chemistry. 1 Introduction 2 CHEM: Total Synthesis 3 BIO-CHEM: Semi-Synthesis 4 CHEM-BIO: Precursor Directed Biosynthesis 5 BIO-CHEM-BIO: Mutasynthesis 6 BIO-BIO: Combinatorial Biosynthesis 7 BIO-BIO-CHEM: Genochemetics: Gene Expression Enabling Synthetic Diversification 8 Conclusions and Future Directions in Natural Product Analogue Generation

Challenges and triumphs to genomics-based natural product discovery

Genome sequencing is rapidly changing the field of natural products research by providing opportunities to assess the biosynthetic potential of strains prior to chemical analysis or biological testing. Ready access to sequence data is driving the development of new bioinformatic tools and methods to identify the products of silent or cryptic pathways. While genome mining has fast become a useful approach to natural product discovery, it has also become clear that identifying pathways of interest is much easier than finding the associated products. This has led to bottlenecks in the discovery process that must be overcome for the potential of genomics-based natural product discovery to be fully realized. In this perspective, we address some of these challenges in the context of our work with the marine actinomycete genus Salinispora, which is proving to be a useful model with which to apply genome mining as an approach to natural product discovery.