Search

The document from Chemical Communications provides a comprehensive list of articles and research findings in the field of chemistry. It covers a wide range of topics such as photodynamic therapy, electrochemical methods for gas detection, and crystallography. The journal aims to showcase original discoveries and preliminary research that contribute to scientific progress. The Royal Society of Chemistry publishes this journal, which connects the global chemistry community and reinvests profits back into the field. [Extracted from the article]

Background: In the search for new antimicrobial secondary metabolites of fungi, optimizing culture conditions remains a critical challenge, as standard laboratory approaches often result in low yields. While non-selective methods, such as modifying culture media, have been effective in expanding the chemical diversity of fungal metabolites, they have not yet established a direct link to key process parameters crucial for further optimization. This study investigates the capacity of Diaporthe caliensis as a biofactory for biologically active secondary metabolites, employing tailored culture media to explore the relationship between chemical diversity and critical process variables. Results: The metabolomic profiles, antibacterial activities, and production yields of the extracts were analyzed to progressively adjust the culture conditions. This study was conducted in five steps, evaluating carbon and nitrogen source concentration, nitrogen source type, salt supplementation, and pH adjustment. Altering the rice starch concentration affected biomass yield per unit of oxygen consumed, while modifications to the nitrogen source concentration influenced both the bioactivity and chemical space by Diaporthe caliensis. Despite changes at the metabolome level, the extracts consistently exhibited potent antibacterial activities, influenced by the nitrogen source, added salts and pH adjustments. For instance, when using corn steep liquor and rice starch, supplemented with micronutrients, different metabolites were produced depending on whether buffer or water was used, though both conditions showed similar antibacterial activities (IC50 ≈ 0.10 mg mL− 1 against Staphylococcus aureus and ≈ 0.14 mg mL− 1 against Escherichia coli). In the treatment where buffer was used to stabilize pH change, there was an increase in the production of phomol-like compounds which are associated with known antibiotic properties. In contrast, in the treatments using water, the drop in pH stimulated the production of previously unidentified metabolites with potential antimicrobial activity. Conclusions: This study proposes a strategic methodology for the tailored formulation of culture media aiming to promote the biosynthesis of diverse secondary metabolites. This approach revealed the critical role of nutrient limitation and pH regulation in stimulating the production of polyketide-lactone derivatives, including the antibiotic phomol. Ultimately, the systematic, custom-designed culture conditions developed in this work offer a promising strategy for expanding the chemical diversity of Diaporthe caliensis, while providing valuable insights into the key parameters needed for optimizing this fungal biofactory. [ABSTRACT FROM AUTHOR]

The delineation of the complex biosynthesis of the potent antibiotic mupirocin, which consists of a mixture of pseudomonic acids (PAs) isolated from Pseudomonas fluorescens NCIMB 10586, presents significant challenges, and the timing and mechanisms of several key transformations remain elusive. Particularly intriguing are the steps that process the linear backbone from the initial polyketide assembly phase to generate the first cyclic intermediate PA‐B. These include epoxidation as well as incorporation of the tetrahydropyran (THP) ring and fatty acid side chain required for biological activity. Herein, we show that the mini‐module MmpE performs a rare online (ACP‐substrate) epoxidation and is integrated ('in‐cis') into the polyketide synthase via a docking domain. A linear polyketide fragment with six asymmetric centres was synthesised using a convergent approach and used to demonstrate substrate flux via an atypical KS0 and a previously unannotated ACP (MmpE_ACP). MmpE_ACP‐bound synthetic substrates were critical in demonstrating successful epoxidation in vitro by the purified MmpE oxidoreductase domain. Alongside feeding studies, these results confirm the timing as well as chain length dependence of this selective epoxidation. These mechanistic studies pinpoint the location and nature of the polyketide substrate prior to the key formation of the THP ring and esterification that generate PA‐B. [ABSTRACT FROM AUTHOR]

Annonaceous acetogenins (ACGs) have potent anti-tumor activity, and the problems of their low solubility, hemolysis, and in vivo delivery have been solved by encapsulation into nanoparticles. However, the high toxicity still limits their application in clinic. In this paper, the co-delivery strategy was tried to enhance the in vivo anti-tumor efficacy and reduce the toxic effects of ACGs. Ginsenoside Rh2, a naturally derived biologically active compound, which was reported to have synergistic effect with paclitaxel, was selected to co-deliver with ACGs. And due to its similarity with cholesterol in chemical structure, the co-loading liposomes, (ACGs + Rh2)-Lipo, were successfully constructed using Rh2 instead of cholesterol as the membrane material. The obtained (ACGs + Rh2)-Lipo and ACGs-Lipo had similar mean particle size (about 80 nm), similar encapsulation efficiency (EE, about 97%) and good stability. The MTS assay indicated that (ACGs + Rh2)-Lipo had stronger toxicity in vitro. In the in vivo study, in contrast to ACGs-Lipo, (ACGs + Rh2)-Lipo demonstrated an improved tumor targetability (3.3-fold in relative tumor targeting index) and significantly enhanced the antitumor efficacy (tumor inhibition rate, 72.9 ± 5.4% vs. 60.5 ± 5.4%, p <.05). The body weight change, liver index, and spleen index of tumor-bearing mice showed that Rh2 can attenuate the side effects of ACGs themselves. In conclusion, (ACGs + Rh2)-Lipo not only alleviated the toxicity of ACGs to the organism, but also enhanced their anti-tumor activity, which is expected to break through their bottleneck. [ABSTRACT FROM AUTHOR]

The new natural products reported in 2023 in peer-reviewed articles in journals with good reputations were reviewed and analyzed. The advances made by Asian research groups in the field of natural products chemistry in 2023 were summarized. Compounds with unique structural features and/or promising bioactivities originating from Asian natural sources were discussed based on their structural classification. [ABSTRACT FROM AUTHOR]

Drug resistance is an important factor in the fight against influenza A virus (IAV). Natural products offer a rich source of lead compounds for the discovery of novel antiviral drugs. In a previous study, we isolated the sorbicillinoid polyketide HSL-2 from the mycelium of fungus Trichoderma sp. T-4-1. Here, we show that this compound exerts strong antiviral activity against a panel of IAVs. The immunofluorescence and qRT-PCR assays were used to detect the inhibitory effect of HSL-2 toward the replication of influenza virus and IAV-induced expression of the pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. The results indicated that HSL-2 inhibited influenza virus replication, and it significantly inhibited IAV-induced overexpression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β through modulating the PPAR-γ/NF-κB pathway. Notably, this effect was decreased when cells were transfected with PPAR-γ siRNA or treated with the PPAR-γ inhibitor T0070907. In addition, HSL-2 was able to attenuate lung inflammatory responses and to improve lung lesions in a mouse model of IAV infection. In this paper, we identified a microbial secondary metabolite, HSL-2 , with anti-influenza virus activity. This report is the first to describe the antiviral activity and mechanism of action of HSL-2 , and it provides a new strategy for the development of novel anti-influenza virus drugs from natural sources. [ABSTRACT FROM AUTHOR]

Histolocalization and quantification of secondary metabolites established the occurrence of alkaloids, phenols and acetogenins in various plant organs of A. muricata at different stages of plant growth.Annona muricata L. possesses broad assemblage of ethno-pharmaceutical and therapeutic upsides ascribed to biosynthesis of secondary metabolites. Currently, the bioactivity is characterized by the production of acetogenins (ACGs), and also by the biosynthesis of alkaloids, primarily benzylisoquinolines derived from tyrosine and phenolic compounds. As a result of high variability of metabolite production in A. muricata, the present study evaluated the histochemical analysis of various plant parts at different developmental stages of growth. Presences of phytometabolites were determined using in-situ histochemical localization of alkaloids, phenolic compounds and acetogenins, while its estimation employing spectroscopic quantification techniques to understand structure, development, time-course deposition, content and distribution of secondary phytoconstituents. Study revealed distinct presence of secondary metabolites in cells and tissues of all plant organs in various intensities and patterns. Alkaloids and acetogenins occurred mostly in secretory cavities or idioblast cells while sparsely associated with other cells or tissues. Phenolic compounds emerged widely, with no confined distribution patterns occurring in storage cells and tissues. Quantitative analysis revealed highest accumulation of alkaloids, phenols and acetogenins in mature root-barks, mature unripe fruit rind and mature leaf respectively. Secondary metabolites generally occurred in young stages at low concentrations as compared to matured growth stages of plant parts. Such in-situ histochemical and biochemical approach will help in identifying the cells and tissues responsible for synthesis, storage and biological effects of potential secondary metabolites which could be further used for culturing and enhancing its production with biotechnological aids. [ABSTRACT FROM AUTHOR]

Fusarium species are commonly found in soil, water, plants, and animals. A variety of secondary metabolites with multiple biological activities have been recently isolated from Fusarium species, making Fusarium fungi a treasure trove of bioactive compounds. This mini-review comprehensively highlights the newly isolated secondary metabolites produced by Fusarium species and their various biological activities reported from 2019 to October 2024. About 276 novel metabolites were revealed from at least 21 Fusarium species in this period. The main metabolites were nitrogen-containing compounds, polyketides, terpenoids, steroids, and phenolics. The Fusarium species mostly belonged to plant endophytic, plant pathogenic, soil-derived, and marine-derived fungi. The metabolites mainly displayed antibacterial, antifungal, phytotoxic, antimalarial, anti-inflammatory, and cytotoxic activities, suggesting their medicinal and agricultural applications. This mini-review aims to increase the diversity of Fusarium metabolites and their biological activities in order to accelerate their development and applications. [ABSTRACT FROM AUTHOR]

Four new polyketides, heterocornol Y (1), stemphyindan (2), pestalospirane C (3), and stemphyspyrane (4), along with five known ones (5–9) were isolated from the endophytic fungus Stemphylium globuliferum 17035 (SG17035) based on the One Strain Many Compounds (OSMAC) strategy allied with an LC-MS approach. These structures were elucidated through extensive spectroscopic analyses, single-crystal X-ray diffraction, and 13C NMR-DP4 analysis. Pestalospirane C (3) and stemphyspyrane (4) featured unprecedented spiroketal skeletons. In addition, the putative biosynthetic logic for compounds 1–4 was proposed. Antibacterial and cytotoxic activities of compounds 1–9 were evaluated. Stemphyspyrane (4) displayed promising antibacterial activity against different pathogens, especially against Staphylococcus aureus, Porphyromonas gingivalis, and methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 3.125 μM, 6.25 μM, and 12.5 μM, respectively. It is promising as an antibacterial agent for further optimization. [ABSTRACT FROM AUTHOR]

Astragalus, a group of legume plants, has a pronounced rhizosphere effect. Many species of Astragalus with limited resource reserves are distributed in the high-altitude area of northern Yunnan, China. Although some of these plants have high medicinal value, the recognition of them is still at a low level. The aim of this research is to explore the species diversity of cultivable rhizofungi derived from Astragalus acaulis, A. forrestii and A. ernestii growing in a special high–cold environment of northwest Yunnan and discover anti-infective components from these fungi. A total of 93 fungal strains belonging to 38 species in 18 genera were isolated and identified. Antibacterial and antimalarial screening yielded 10 target strains. Among them, the ethyl acetate crude extract of the fermented substrate of the rhizofungus Aspergillus calidoustus AA12 derived from the plant A. acaulis showed broad-spectrum antibacterial activity and the best antimalarial activity. Further chemical investigation led to the first discovery of seven compounds from the species A. calidoustus, including sesterterpine 6-epi-ophiobolin G; three sesquiterpenes, penicisochroman A, pergillin and 7-methyl-2-(1-methylethylethlidene)-furo [3,2-H]isoquinoline-3-one; and three polyketides, trypacidin, 1,2-seco-trypacidin and questin. Among them, the compound 6-epi-ophiobolin G exhibited moderate to strong antibacterial activity against six Gram-positive pathogens with the minimum inhibitory concentration (MIC) ranging from 25 to 6.25 μg/mL and a prominent inhibitory effect on the biofilm of Streptococcus agalactiae at an MIC value of 3.125 μg/mL. This compound also displayed potent antimalarial activity against Plasmodium falciparum strains 3D7 and chloroquine-resistant Dd2 at the half-maximal inhibitory concentration (IC50) values of 3.319 and 4.340 µmol/L at 72 h, respectively. This study contributed to our understanding of the cultivable rhizofungi from characteristic Astragalus plants in special high–cold environments and further increased the library of fungi available for natural anti-infectious product screening. [ABSTRACT FROM AUTHOR]

Malonyl‐coenzyme A (CoA) is a key precursor for the biosynthesis of multiple value‐added compounds by microbial cell factories, including polyketides, carboxylic acids, biofuels, and polyhydroxyalkanoates. Owing to its role as a metabolic hub, malonyl‐CoA availability is limited by competition in several essential metabolic pathways. To address this limitation, we modified a genome‐reduced Pseudomonas putida strain to increase acetyl‐CoA carboxylation while limiting malonyl‐CoA utilization. Genes involved in sugar catabolism and its regulation, the tricarboxylic acid (TCA) cycle, and fatty acid biosynthesis were knocked‐out in specific combinations towards increasing the malonyl‐CoA pool. An enzyme‐coupled biosensor, based on the rppA gene, was employed to monitor malonyl‐CoA levels in vivo. RppA is a type III polyketide synthase that converts malonyl‐CoA into flaviolin, a red‐colored polyketide. We isolated strains displaying enhanced malonyl‐CoA availability via a colorimetric screening method based on the RppA‐dependent red pigmentation; direct flaviolin quantification identified four engineered strains had a significant increase in malonyl‐CoA levels. We further modified these strains by adding a non‐canonical pathway that uses malonyl‐CoA as precursor for poly(3‐hydroxybutyrate) biosynthesis. These manipulations led to increased polymer accumulation in the fully engineered strains, validating our general strategy to boost the output of malonyl‐CoA–dependent pathways in P. putida. [ABSTRACT FROM AUTHOR]

Fungi generate a diverse array of bioactive compounds with significant pharmaceutical applications. However, the chemical diversity of natural products in fungi remains largely unexplored. Here, we present a paradigm for specifically discovering diverse and bioactive compounds from fungi by integrating genome mining with building block molecular network and coculture analysis. Through pangenome and sequence similarity network analysis, we identified a rare type I polyketide enzyme from Penicillium sp. ZJUT-34. Subsequent building block molecular network and coculture strategy led to the identification and isolation of a pair of novel polyketides, (±)-peniphenone E [(±)−1], three known polyketides (2–4), and three precursor compounds (5–7) from a combined culture of Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. Their structures were established through extensive spectroscopic analysis, including NMR and HRESIMS. Chiral HPLC separation of compound 1 yielded a pair of enantiomers (+)−1 and (−)−1, with their absolute configurations determined using calculated ECD methods. Compound (±)−1 is notable for its unprecedented structure, featuring a unique 2-methyl-hexenyl-3-one moiety fused with a polyketide clavatol core. We proposed a hypothetical biosynthetic pathway for (±)−1. Furthermore, compounds 2, 5, and 6 exhibited strong antioxidant activity, whereas (−)−1, (+)−1, 3, and four exhibited moderate antioxidant activity compared to the positive control, ascorbic acid. Our research demonstrates a pioneering strategy for uncovering novel polyketides by merging genome mining, metabolomics, and cocultivation methods. This approach addresses the challenge of discovering natural compounds produced by rare biosynthetic enzymes that are often silent under conventional conditions due to gene regulation. IMPORTANCE Polyketides, particularly those with complex structures, are crucial in drug development and synthesis. This study introduces a novel approach to discover new polyketides by integrating genomics, metabolomics, and cocultivation strategies. By combining genome mining, building block molecular networks, and coculturing techniques, we identified and isolated a unique polyketide, (±)-peniphenone E, along with three known polyketides and three precursor compounds from Penicillium sp. ZJUT-34 and Penicillium sp. ZJUT23. This approach highlights the potential of using combined strategies to explore fungal chemical diversity and discover novel bioactive compounds. The successful identification of (±)-peniphenone E, with its distinctive structure, demonstrates the effectiveness of this integrated method in enhancing natural product discovery and underscores the value of innovative approaches in natural product research. [ABSTRACT FROM AUTHOR]

Secondary metabolites often function as antipredator defenses, but when bioactive at low concentrations, their off-target effects on other organisms may be overlooked. Candidate "keystone molecules" are proposed to affect community structure and ecosystem functions, generally originating as defenses of primary producers; the broader effects of animal chemistry remain largely unexplored, however. Here, we characterize five previously unreported polyketides (alderenes A to E) biosynthesized by sea slugs reaching exceptional densities (up to 9000 slugs per square meter) in Northern Hemisphere estuaries. Alderenes comprise only 0.1% of slug wet weight, yet rendered live slugs or dead flesh unpalatable to three co-occurring consumers, making a potential food resource unavailable and redirecting energy flow in critical nursery habitat. Alderenes also displaced infauna from the upper sediment of the mudflat but attracted ovipositing snails. By altering communities, such compounds may have unexpected cascading effects on processes ranging from bioturbation to reproduction of species not obviously connected to the producing organisms, warranting greater attention by ecologists. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of death worldwide. Also threatening the public is the emergence of antibiotic resistance to existing medicines. Despite the challenge to produce viable natural products to market, there continues to be a need within public health to provide new chemotherapeutic drugs such as those exhibiting cytotoxicity and tumor cell growth-inhibitory properties. As marine genomic research advances, it is apparent that marine-derived sediment harbors uniquely potent bioactive compounds compared to their terrestrial counterparts. The Streptomyces genus in particular produces more than 30% of all secondary metabolites currently approved for human health, thus harboring unexplored reservoirs of chemotherapeutic and antibiotic agents to combat emerging disease. The present study identifies the presence of Streptomyces hygroscopicus and rapamycinicus in environmental sediment at locations within the U.S. Stellwagen Bank National Marine Sanctuary (SBNMS) from 2017 to 2022. Sequencing and bioinformatics methods catalogued biosynthetic gene clusters (BGCs) that drive cytotoxic and antibiotic biochemical processes in samples collected from sites permittable and protected to fishing activity. Poisson regression models confirmed that Sites 1 and 3 had significantly higher occurrences of rapamycinicus than other sites (p < 0.01). Poisson regression models confirmed that Sites 1, 2 and 3 had significantly higher occurrence for Streptomyces hygroscopicus across sites (p < 0.05). Interestingly, permitted fishing sites showed a greater prevalence of both species. Statistical analyses showed a significant difference in aligned hits with polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) by site and between species with hygroscopicus showing a greater quantity than rapamycinicus among Streptomyces spp. (p < 0.05; F = 4.7 > F crit). [ABSTRACT FROM AUTHOR]

Finding new molecules to prevent the growth of antimicrobial resistance is a hot topic for scientists worldwide. It has been reported that some raw bioproducts containing Monascus polyketides have antimicrobial activities, but extensive studies on this effect have not been conducted. In this context, our studies aimed to evaluate the antimicrobial properties of six raw bioproducts containing three classes of microbial polyketides biosynthesized by three Monascus strains through solid-state biosynthesis. As a methodology, we performed in silico predictions using programs such as PyMOL v3.0.4 and employed ESI-MS techniques to provide evidence of the presence of the six studied compounds in our bioproducts. The results obtained in silico were validated through in vitro studies using the Kirby-Bauer diffusion method on bacteria and fungi. The test performed in silico showed that Monascorubramine has the highest affinity for both Gram-positive and Gram-negative bacteria, followed by yellow polyketides such as Ankaflavin and Monascin. The estimated pharmacokinetic parameters indicated high gastrointestinal absorption and the potential to cross the blood-brain barrier for all studied compounds. However, the compounds also inhibit most enzymes involved in drug metabolism, presenting some level of toxicity. The best in vitro results were obtained for S. aureus, with an extract containing yellow Monascus polyketides. Predictions made for E. coli were validated in vitro for P. aeruginosa, S. enterica, and S. marcescens, as well as for fungi. Significant antibacterial properties were observed during this study for C. albicans, S. aureus, and fungal dermatophytes for crude bioproducts containing Monascus polyketides. In conclusion, the antimicrobial properties of Monascus polyketides were validated both in silico and in vitro. However, due to their potential toxicity, these bioproducts would be safer to use as topical formulations. [ABSTRACT FROM AUTHOR]

The Yamaguchi reagent, based on 2,4,6-trichlorobenzoyl chloride (TCBC) and 4-dimethylaminopyridine (DMAP), is an efficient tool for conducting the intermolecular (esterification) reaction between an acid and an alcohol in the presence of a suitable base (Et3N or iPr2NEt) and solvent (THF, DCM, or toluene). The Yamaguchi protocol is renowned for its ability to efficiently produce a diverse array of functionalized esters, promoting high yields, regioselectivity, and easy handling under mild conditions with short reaction times. Here, the recent utilization of the Yamaguchi reagent was reviewed in the synthesis of various natural products such as macrolides, terpenoids, polyketides, peptides, and metabolites. [ABSTRACT FROM AUTHOR]

Background: Marine actinomycetes, especially Streptomyces, are recognized as excellent producers of diverse and bioactive secondary metabolites on account of the multiplicity of marine habitations and unique ecological conditions, which are yet to be explored in terms of taxonomy, ecology, and functional activity. Isolation, culture and genome analysis of novel species of Streptomyces to explore their potential for discovering bioactive compounds is an important approach in natural product research. Results: A marine actinobacteria, designated strain SCSIO 75703 T, was isolated, and the potential for bioactive natural product discovery was evaluated based on genome mining, compound detection, and antimicrobial activity assays. The phylogenetic, phenotypic and chemotaxonomic analyses indicate that strain SCSIO 75703 T represents a novel species in genus Streptomyces, for which the name Streptomyces sediminicola sp. nov. is proposed. Genome analysis revealed the presence of 25 secondary metabolite biosynthetic gene clusters. The screening for antibacterial activity reveals the potential to produce bioactive metabolites, highlighting its value for in-depth exploration of chemical constituents. Seven compounds (1–7) were separated from the fractions guided by antibacterial activities, including three indole alkaloids (1–3), three polyketide derivatives (4–6), and 4-(dimethylamino)benzoic acid (7). These primarily antibacterial components were identified as anthracimycin (4), 2-epi-anthracimycin (5) and β-rubromycin (6), presenting strong antibacterial activities against Gram-positive bacteria with the MIC value ranged from 0.125 to 16 μg/mL. Additionally,, monaprenylindole A (1) and 3-cyanomethyl-6-prenylindole (2) displayed moderate inhibitory activities against α-glucosidase with the IC50 values of 83.27 and 86.21 μg/mL, respectively. Conclusion: Strain SCSIO 75703 T was isolated from marine sediment and identified as a novel species within the genus Streptomyces. Based on genomic analysis, compounds isolation and bioactivity studies, seven compounds were identified, with anthracimycin and β-rubromycin showing significant biological activity and promising potential for further applications. [ABSTRACT FROM AUTHOR]

Four new lactones, including hypomonacid A (1) and hypomonone A–C (4–6), as well as nine known polyketide analogues (2–3 and 7–13) were obtained from endophytic fungus Hypomontagnella sp. TX-09 derived from Santalum album. Their planar structures were extensively established by analysing HRESIMS and NMR spectroscopic data. Stereochemistry of new compounds was determined by X-ray diffraction analysis and modified Mosher’s method in combination with quantum-chemical ECD calculation. In addition, compounds 1 and 2 showed anti-inflammatory activity by inhibition of lipopolysaccharide (LPS)-induced NO production in RAW264.7 cells at 50 μmol/L without cytotoxicity. Among them, compound 1 inhibited the production of LPS-stimulated inflammation in mouse macrophage RAW264.7 cells by suppressing the expression of iNOS, TNF-α, IL-1β, and IL-6. [ABSTRACT FROM AUTHOR]

Two novel polyketides, called colletotrikalactones A and B (1 and 2), together with eleven known compounds (3–13) were isolated from the culture broth of the mangrove associated fungus Colletotrichum sp. J065. Compounds 1 and 2 featured a rare 5/6/10-fused tricyclic scaffold. The new structures were elucidated through comprehensive spectroscopic analyses and chemical transformation. [ABSTRACT FROM AUTHOR]

After half a century from their isolation in 1974, we report the first total syntheses of β‐ and γ‐naphthocyclinones, two dimeric pyranonaphthoquinones featuring an unusual bicyclo[3.2.1]‐octadienone core. The syntheses were achieved with full stereochemical control and functional group management, relying on 1) enantioselective construction of the bicyclic core by Rh‐catalyzed enantioselective 1,4‐addition followed by thiolate‐mediated reductive cyclization, and 2) judicious design of a common chiral, non‐racemic monomer unit that is capable of divergence into the donor and acceptor units, and reunion to construct the bicyclo[3.2.1]octadienone core. [ABSTRACT FROM AUTHOR]

Background: Sequencing and annotating genomes of non-model organisms helps to understand genome architecture, the genetic processes underlying species traits, and how these genes have evolved in closely-related taxa, among many other biological processes. However, many metazoan groups, such as the extremely diverse molluscs, are still underrepresented in the number of sequenced and annotated genomes. Although sequencing techniques have recently improved in quality and quantity, molluscs are still neglected due to difficulties in applying standardized protocols for obtaining genomic data. Results: In this study, we present the chromosome-level genome assembly and annotation of the sacoglossan sea slug species Elysia timida, known for its ability to store the chloroplasts of its food algae. In particular, by optimizing the long-read and chromosome conformation capture library preparations, the genome assembly was performed using PacBio HiFi and Arima HiC data. The scaffold and contig N50s, at 41.8 Mb and 1.92 Mb, respectively, are approximately 30-fold and fourfold higher compared to other published sacoglossan genome assemblies. Structural annotation resulted in 19,904 protein-coding genes, which are more contiguous and complete compared to publicly available annotations of Sacoglossa with respect to metazoan BUSCOs. We found no evidence for horizontal gene transfer (HGT), i.e. no photosynthetic genes encoded in the sacoglossan nucleus genome. However, we detected genes encoding polyketide synthases in E. timida, indicating that polypropionates are produced. HPLC–MS/MS analysis confirmed the presence of a large number of polypropionates, including known and yet uncharacterised compounds. Conclusions: We can show that our methodological approach helps to obtain a high-quality genome assembly even for a "difficult-to-sequence" organism, which may facilitate genome sequencing in molluscs. This will enable a better understanding of complex biological processes in molluscs, such as functional kleptoplasty in Sacoglossa, by significantly improving the quality of genome assemblies and annotations. [ABSTRACT FROM AUTHOR]

Cerulenin (1) is the first reported natural fatty acid synthase inhibitor and has been intensively researched for its antifungal, anticancer and anti‐obesity properties. However, the molecular basis for its biosynthesis has remained a mystery for six decades. Here, we have identified the polyketide biosynthetic gene cluster (cer) responsible for the biosynthesis of 1 from two Sarocladium species using a self‐resistance gene mining approach, which we validated via heterologous reconstitution of cer cluster in an Aspergillus nidulans host. Expression of various combinations of cer genes uncovered key pathway intermediates, electrocyclisation products derived from PKS‐encoded polyenoic acids, and a suite of 13 new analogues of 1. This enabled us to establish a biosynthetic pathway to 1 that starts with a C12 polyketide precursor containing both E and Z double bonds and involves a complex series of epoxidations, double bond shifts, E/Z isomerisation and epoxide reduction. Using in vitro assays, we further validated the roles of amidotransferase CerD in amidation, and oxidase CerF and reductase CerE in the final two‐electron oxidation and enone reduction steps towards 1. These findings expand our understanding of complex tailoring modifications in highly reducing PKS pathways and pave the way for the engineered biosynthesis of cerulenin analogues. [ABSTRACT FROM AUTHOR]

Angucyclines and angucyclinones represent a class of natural compounds that belong to the group of aromatic polyketides. They exhibit a wide array of biological properties, such as antimicrobial, antiviral, and cytotoxic. Their considerable therapeutic potential and diverse scaffolds have attracted many synthetic chemists to devise novel strategies to construct their intricate molecular architecture. Over 300 class members have been isolated from natural sources, mainly from bacterial strains of Streptomyces species. This review highlights recent advancements in their synthesis, such as oxidative cyclization, photooxidation, and metal‐catalyzed [4+2]‐cycloaddition, which has facilitated the efficient and practical total syntheses of various angucycline and angucyclinone natural products. [ABSTRACT FROM AUTHOR]

Summary: Human breast milk is a complex fluid rich in bioactive molecules crucial for infant growth and development. Global health organisations recommend exclusive breastfeeding to optimise infant health. In cases where maternal milk is unavailable, donor breast milk from human milk banks (HMBs) serves as an essential alternative. Currently, human breast milk preservation relies on Holder pasteurisation (HoP), which, while effective at pathogen inactivation, can compromise breast milk's nutritional and biological properties. High‐pressure processing (HPP) is an alternative pasteurisation method that utilises high pressure to kill pathogens without degrading nutrition. This study examined HPP's impact on donor breast milk lipids, sugars and antioxidants. Metabolomics reveals diverse bioactive compounds, including lipids, polyphenols and polyketides, elucidating breast milk's complexity. Some lipid subclasses respond to HPP; ceramides decreased under both treatments, while fatty aldehydes and esters increased under specific HPP conditions. Additionally, we quantified oxidised lipids, notably dietary oxysterols (DOxS), known for pro‐oxidant and pro‐inflammatory properties. These findings enhance understanding of HPP targeted approaches and breast milk's complexity, contributing to innovative milk preservation techniques that could advance specialised infant nutrition and assist donor milk banking systems. [ABSTRACT FROM AUTHOR]

Trialeurodes vaporariorum Westwood poses a significant threat to vegetable and ornamental crops in temperate zones, resulting in notable reductions in yield and substantial economic burdens. In order to find compounds with high insecticidal activity against T. vaporariorum, five compounds were isolated and identified from the crude extract of Streptomyces sp. SA61. These include three new polyketides, named strekingmycins F–H (1–3); one new diterpenoid, named phenalinolactone CD8 (4); and one known compound, strekingmycin A (5). Their structures were analyzed using high-resolution electrospray ionization mass spectrometry and one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy data and by comparing them with previously reported data. The insecticidal activities of compounds 1–5 against T. vaporariorum were evaluated. Among them, compound 5 exhibited the highest insecticidal activity, with an LC50 of 6.949 mg/L against T. vaporariorum at 72 h using the leaf-dip method. Lower insecticidal activities were found in compounds 1–4, with LC50 values of 22.817, 19.150, 16.981 and 41.501 mg/L, respectively. These data indicate that strekingmycin could be a potential candidate for a novel insecticide to control T. vaporariorum. [ABSTRACT FROM AUTHOR]

Bacterial infections pose a significant clinical burden on global health. The growing incidence of drug-resistant pathogens highlights the critical necessity to identify and isolate bioactive compounds from marine resources. Marinederived fungi could provide novel lead compounds against pathogenic bacteria. Due to the particularity of the marine environment, Aspergillus species derived from marine sources have proven to be potent producers of bioactive secondary metabolites and have played a considerable role in advancing drug development. This study reviews the structural diversity and activities against pathogenic bacteria of secondary metabolites isolated from marine-derived Aspergillus species over the past 14 years (January 2010-June 2024), and 337 natural products (including 145 new compounds) were described. The structures were divided into five major categories--terpenoids, nitrogen-containing compounds, polyketides, steroids, and other classes. These antimicrobial metabolites will offer lead compounds to the development and innovation of antimicrobial agents. [ABSTRACT FROM AUTHOR]

Four new lactones, including hypomonacid A (1) and hypomonone A–C (4–6), as well as nine known polyketide analogues (2–3 and 7–13) were obtained from endophytic fungus Hypomontagnella sp. TX-09 derived from Santalum album. Their planar structures were extensively established by analysing HRESIMS and NMR spectroscopic data. Stereochemistry of new compounds was determined by X-ray diffraction analysis and modified Mosher’s method in combination with quantum-chemical ECD calculation. In addition, compounds 1 and 2 showed anti-inflammatory activity by inhibition of lipopolysaccharide (LPS)-induced NO production in RAW264.7 cells at 50 μmol/L without cytotoxicity. Among them, compound 1 inhibited the production of LPS-stimulated inflammation in mouse macrophage RAW264.7 cells by suppressing the expression of iNOS, TNF-α, IL-1β, and IL-6.

Comparison of biosynthetic gene clusters (BGCs) found in devastating plant pathogens and biocontrol fungi revealed an uncharacterized and conserved polyketide BGC. Genome mining identified the associated metabolite to be treconorin, which has a terpene-like, trans-fused 5,7-bicyclic core that is proposed to derive from a (4 + 3) cycloaddition. The core is esterified with d-glucose, which derives from the glycosidic cleavage of a trehalose ester precursor. This glycomodification strategy is different from the commonly observed glycosylation of natural products.

Type I polyketide synthases (T1PKSs) hold enormous potential as a rational production platform for the biosynthesis of specialty chemicals. However, despite great progress in this field, the heterologous expression of PKSs remains a major challenge. One of the first measures to improve heterologous gene expression can be codon optimization. Although controversial, choosing the wrong codon optimization strategy can have detrimental effects on the protein and product levels. In this study, we analyzed 11 different codon variants of an engineered T1PKS and investigated in a systematic approach their influence on heterologous expression in Corynebacterium glutamicum, Escherichia coli, and Pseudomonas putida. Our best performing codon variants exhibited a minimum 50-fold increase in PKS protein levels, which also enabled the production of an unnatural polyketide in each of these hosts. Furthermore, we developed a free online tool (https://basebuddy.lbl.gov) that offers transparent and highly customizable codon optimization with up-to-date codon usage tables. In this work, we not only highlight the significance of codon optimization but also establish the groundwork for the high-throughput assembly and characterization of PKS pathways in alternative hosts.

Polyketide retrobiosynthesis, where the biosynthetic pathway of a given polyketide can be reversibly engineered due to the colinearity of the polyketide synthase (PKS) structure and function, has the potential to produce millions of organic molecules. Mixing and matching modules from natural PKSs is one of the routes to produce many of these molecules. Evolutionary analysis of PKSs suggests that traditionally used module boundaries may not lead to the most productive hybrid PKSs and that new boundaries around and within the ketosynthase domain may be more active when constructing hybrid PKSs. As this is still a nascent area of research, the generality of these design principles based on existing engineering efforts remains inconclusive. Recent advances in structural modeling and synthetic biology present an opportunity to accelerate PKS engineering by re-evaluating insights gained from previous engineering efforts with cutting edge tools.

Comprehensive Summary: Four polycyclic ten‐membered lactones possessing unprecedented 10/6/5 tricyclic ring skeleton, named eutypetides A—D (1—4), and an intriguing polyketide containing a hexahydroisobenzofuran‐1(3H)‐one motif, named eutypetide E (5) were isolated from the marine‐derived fungus Eutypella sp. F0219, together with three new related biosynthetic polyketides eutypetides F—H (6—8). The absolute configurations of 1—5 were unequivocally determined by single‐crystal X‐ray diffraction analyses (Cu Kα), modified Mosher's method and electronic circular dichroism (ECD) calculations. Eutypetides G (7) showed remarkable anti‐inflammatory activity and could reduce the mRNA expression of proinflammatory cytokines IL‐1β, IL‐6, TNF‐α, and iNOS induced by LPS. Most notably, compounds 1—4 were formed biogenetically from 6—7 via the key intramolecular [4+2] cycloaddition, while compound 5 could be constructed biogenetically from 8 through the intramolecular [4+2] cycloaddition. All the above eight polyketides are proposed to originate from a C10 and a C6 fatty acid. [ABSTRACT FROM AUTHOR]

The coastal region of the Caribbean is notable for the chemical diversity found in its sponge products, resulting in the biosynthesis of a range of natural marine products, including polyketides. The objective of this manuscript is to summarize the isolated polyketides from sponges of the genus Plakortis located around the Caribbean coasts. This review provides a comprehensive overview of specimen location, isolation procedures, characterization methods, and biological assay studies of about 95 polyketides isolated from 1978 to 2024 in the Caribbean coasts of The Bahamas, Cayman Islands, Belize, Dominica, Jamaica, Martinique, Panamá, Puerto Rico, and Tobago. The Caribbean polyketides have been isolated from different types of Plakortis sp., such as P. simplex, P. halichondroides, P. zyggompha, and P. angulospiculatus, which have demonstrated antimicrobial, anticancer, anti-inflammatory, antiparasitic, and antiviral activities. A variety of linear polyketides with different functionalities have been reported, including endoperoxides (1,2-dioxane), lactones, indane-type bicyclics (spiculane and zyggomphic), alcohols, alkenes, styryl groups, α,β-unsaturated carboxylic acids, and ketones, as well as related natural products of biosynthetic origin. The aim is to encourage further exploration by researchers in the Caribbean’s coastal marine environments, promoting the discovery and investigation of novel polyketide cyclic peroxides and related secondary metabolites to identify additional bioactive medicinal natural products.

In this overview, naturally occurring resorcylic lactones biosynthetically derived from alternariol and almost exclusively produced by fungi, are discussed with view on their isolation, structure, biological activities, biosynthesis, and total syntheses. This class of compounds consists until now of 127 naturally occurring compounds, with very divers structural motifs. Although only a handful of these toxins (i.e., alternariol and its 9-O-methyl ether, altenusin, dehydroaltenusin, altertenuol, and altenuene) were frequently found and isolated as fungal contaminants in food and feed and have been investigated in significant detail, further metabolites, which were much more rarely found as natural products, similarly show interesting biological activities.

Abstract Background Effective control of shot-hole disease in flowering cherries is challenging because of multiple causative pathogens (bacteria and fungi). Bacillus species are well-known for their ability to control plant pathogens; therefore, biological control potential of a Bacillus isolate, B. velezensis 8–2, against SH disease on flowering cherry trees was investigated. Results This study revealed strong antimicrobial activity of Bacillus velezensis 8–2 against various plant pathogenic bacteria and fungi, particularly focusing on Xanthomonas arboricola pv. pruni (Xap) and Mycosphaerella cerasella (Mc), which cause shot-hole (SH) disease in flowering cherry trees. In vitro assays showed that the fermentation filtrate of B. velezensis 8–2 inhibited bacterial and fungal growth with minimum inhibitory concentrations of 1.25–10% and 2.5–10%, respectively. UPLC-Q–Orbitrap–MS analysis revealed that B. velezensis 8–2 produced antagonistic compounds, including polyketides (difficidin and oxydifficidin) and cyclic lipopeptides (iturin A, fengycin, and surfatin). To enhance antimicrobial activity, fermentation parameters for optimal production of two antibacterial and three antifungal compounds were investigated in a 5 L jar fermenter. By regulating the agitation speed to sustain the state of vegetative cells, the production period was extended by 20 h at 400 rpm, resulting in maximum yields of 86.6 μg/mL for difficidin and 150.0 μg/mL for oxydifficidin within a 72 h fermentation period. In a field trial, a 500-fold diluted 10% suspension concentrate formulation of B. velezensis 8–2 effectively inhibited the development of SH disease, demonstrating 66.6% disease control and a 90.2% disease symptoms reduction. Conclusions This is the first report to assess the disease control efficacy of B. velezensis for the biocontrol of SH disease in the field. These results suggest that the application of B. velezensis 8–2 could serve as a practical alternative for managing various bacterial and fungal diseases, including the management of SH disease in flowering cherry trees. Graphical Abstract

The leinamycin family of polyketides are promising antitumor antibiotics, yet several aspects of their biosynthesis remain elusive. All leinamycin family members bear a sulfur‐containing moiety which is essential for the anticancer activity exhibited by leinamycin. The key building blocks required for the incorporation of these functionalities are introduced in the final module of the polyketide synthase (PKS), which elegantly combines β‐branching and thiocysteine incorporation to generate a diverse library of sulfur‐based molecular scaffolds. Two acyl carrier proteins (ACPs) form a key didomain component of this module, but their amino acid sequence divergence has brought into question the common notion of functional equivalence. Here, we provide unprecedented functional evidence that these tandem ACPs play distinct roles in the final module of polyketide assembly. Using the weishanmycin biosynthetic pathway as a template, the in vitro reconstitution of key polyketide chain extension and β‐branching steps in this module has revealed strict functional selectivity for a single ACP. Furthermore, we propose a cryptic transacylation step must occur prior to polyketide off‐loading and cyclization. Altogether, these mechanistic investigations suggest that an atypical in‐series mechanism underpins sulfur incorporation in the leinamycin family, and provides significant progress towards delineating their late‐stage assembly. [ABSTRACT FROM AUTHOR]

The Streptomyces sp. is considered the vast reservoir of bioactive natural products belonging to different classes like polyketides, terpenoids, lanthipeptides, and non-ribosomal peptides to name a few. The ubiquitous distribution of the genus makes them capable of producing distinct compounds. Many of those compounds contain a unique γ-pyrone with various chemical structures and exhibit different bioactivities. One such class, nitrophenyl-γ-pyrone, constitutes different bioactive compounds isolated from Streptomyces sp. from different sources ranging from soil to marine environments. In addition, such compounds have antinematodal, cytotoxicity activities, and inhibition of adipogenesis. These compounds include aureothin (3), spectinabilin (7), and their derivatives. Moreover, there are other compounds like actinopyrones (11–16), benwamycins (22–23), and peucemycin and its derivatives (24–26) that also have antibacterial and anticancer activities. The other group classified as anthra-γ-pyrone has various bioactive natural products. For instance, tetrahydroanthra-γ-pyrone, shellmycin A-D (27–30) possess antibacterial as well as anticancer activities. In addition, the pluramycin family compounds belonging to anthra-γ-pyrone group also possess cytotoxic activity, for instance, kidamycin (31), rubiflavin, and their derivatives (33–37). Xanthones are another important group of natural products that also contain γ-pyrone ring producing different bioactivities. Albofungin (42) and its derivatives (43–46) belong to subgroup polycyclic tetrahydro xanthones that possess antibacterial, anticancer, and antibiofilm, antimacrofouling activities. Similarly, other compounds, belonging to this subgroup, exhibit different bioactivities like antifungal, antimalarial, and antibacterial activities and block transient receptor potential vanilloid 1 (TRPV1). These compounds include cervinomycins (48–55), citreamycins (56–57), sattahipmycin (59), and chrexanthomycins (60–63). This review gives succinct information on the γ-pyrone containing natural products isolated from Streptomyces sp. focusing on their structure and bioactivities. Key points: • The Streptomyces sp. is the producer of various bioactive natural products including the one with γ-pyrone ring. • These γ-pyrone compounds are structurally different and possess different bioactivities. • The Streptomyces has the potential to produce such compounds and the reservoir of these compounds is expected to increase in the future. [ABSTRACT FROM AUTHOR]

Copyright of Food & Fermentation Industries is the property of Food & Fermentation Industries and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Bioinformatic analysis revealed that the genomes of ubiquitous Penicillium spp. might carry dozens of biosynthetic gene clusters (BGCs), yet many clusters have remained uncharacterized. In this study, a detailed investigation of co-culture fermentation including the basidiomycete Armillaria mellea CPCC 400891 and the P. brasilianum CGMCC 3.4402 enabled the isolation of five new compounds including two bisabolene-type sesquiterpenes (arpenibisabolanes A and B), two carotane-type sesquiterpenes (arpenicarotanes A and B), and one polyketide (arpenichorismite A) along with seven known compounds. The assignments of their structures were deduced by the extensive analyses of detailed spectroscopic data, electronic circular dichroism spectra, together with delimitation of the biogenesis. Most new compounds were not detected in monocultures under the same fermentation conditions. Arpenibisabolane A represents the first example of a 6/5-fused bicyclic bisabolene. The bioassay of these five new compounds exhibited no cytotoxic activities in vitro against three human cancer cell lines (A549, MCF-7, and HepG2). Moreover, sequence alignments and bioinformatic analysis to other metabolic pathways, two BGCs including Pb-bis and Pb-car, responsible for generating sesquiterpenoids from co-culture were identified, respectively. Furthermore, based on the chemical structures and deduced gene functions of the two clusters, a hypothetic metabolic pathway for biosynthesizing induced sesquiterpenoids was proposed. These results demonstrated that the co-culture approach would facilitate bioprospecting for new metabolites even from the well-studied microbes. Our findings would provide opportunities for further understanding of the biosynthesis of intriguing sesquiterpenoids via metabolic engineering strategies. Key points: • Penicillium and Armillaria co-culture facilitates the production of diverse secondary metabolites • Arpenibisabolane A represents the first example of 6/5-fused bicyclic bisabolenes • A hypothetic metabolic pathway for biosynthesizing induced sesquiterpenoids was proposed [ABSTRACT FROM AUTHOR]

The macrocyclic tumonolide (1) with enamide functionality and the linear tumonolide aldehyde (2) are new interconverting natural products from a marine cyanobacterium with a peptide‐polyketide skeleton, representing a hybrid of apratoxins and palmyrolides or laingolides. The planar structures were established by NMR and mass spectrometry. The relative configuration of the stereogenically‐rich apratoxin‐like polyketide portion was determined using J‐based configuration analysis. The absolute configuration of tumonolide (1) was determined by chiral analysis of the amino acid units and computational methods, followed by NMR chemical shift and ECD spectrum prediction, indicating all‐R configuration for the polyketide portion, as in palmyrolide A and contrary to the all‐S configuration in apratoxins. Functional screening against a panel of 168 GPCR targets revealed tumonolide (1) as a selective antagonist of TACR2 with an IC50 of 7.0 μM, closely correlating with binding affinity. Molecular docking studies established the binding mode and rationalized the selectivity for TACR2 over TACR1 and TACR3. RNA sequencing upon treatment of HCT116 colorectal cancer cells demonstrated activation of the pulmonary fibrosis idiopathic signaling pathway and the insulin secretion signaling pathway at 20 μM, indicating its potential to modulate these pathways. [ABSTRACT FROM AUTHOR]

The synthesis of biomimetic thioesters for enzymatic studies of ketoreductase (KR) domains from polyketide synthases is described. A TBS-protected dihydroxyalkene fragment was synthesised by a sequence involving a Nagao acetate aldol reaction, a Mukaiyama propionate aldol reaction, and a methylene Wittig olefination. Fragment coupling to N -acetylcysteamine (SNAC) (E)-3-hydroxyhex-4-enethioates by an olefin cross-metathesis (OCM) and subsequent deprotection gave the potential KR product stereoisomers. An analogous OCM with a SNAC (E)-3-ketohex-4-enethioate did not give the desired KR precursor, but the reaction could successfully be replaced by a Horner–Wadsworth–Emmons olefination between a SNAC 3-ketothioester phosphonate and a TBS-protected dihydroxy aldehyde. After deprotection, an intramolecular cyclisation was observed that needs to be considered as a spontaneous side reactivity in the enzymatic assays. [ABSTRACT FROM AUTHOR]

Simple Summary: This study explores whether Escherichia coli carrying the polyketide synthetase (pks) gene cluster in colorectal cancer (CRC) liver metastasis tissues influence immune responses and cancer recurrence patterns. Analyzing tissues from 239 patients, we found that pks+ E. coli was present in 66.7% of liver metastasis cases. Higher levels of pks+ E. coli were associated with lower levels of the serum C-reactive protein, fewer densities of CD4+ cells and CD163+ cells in the tumor microenvironment, and a reduction in the number of organs affected by recurrent metastasis. These findings suggest that pks+ E. coli may influence both systemic and local immune responses, potentially reducing the diversity of affected metastatic organs. Colibactin, a genotoxin produced by Escherichia coli strains harboring the polyketide synthetase (pks) gene cluster, causes DNA damage and somatic mutations. pks+ E. coli is enriched in primary colorectal cancer (CRC) and is associated with clonal driver mutations, but its role in CRC liver metastasis is unclear. We assessed the association of pks+ E. coli in CRC liver metastasis tissues with systemic and local immune responses and the number of organs involved in recurrence using specimens and clinicopathological data from 239 patients with CRC liver metastasis who underwent metastasectomy. The levels of pks+ E. coli in fresh-frozen specimens were quantified as "very low" (<50th percentile), "low" (50th to 75th percentiles), and "high" (>75th percentile) using a digital PCR. Immunohistochemical analysis of tumor-infiltrating immune cells was performed using tissue microarrays. Systemic inflammation was evaluated using serum C-reactive protein (CRP) levels. pks+ E. coli was detected in 66.7% (157 of 239) liver metastasis tissues. Higher levels of pks+E. coli were associated with decreased serum CRP levels and reduced densities of CD4+ cells and CD163+ cells in the tumor-immune microenvironment. The "high" pks+ E. coli group had fewer metastatic organs involved than the "very low" pks+ E. coli group (mean number of organs: 1.00 vs. 1.23). These findings suggest that pks+ E. coli play a modulating role in CRC metastasis. [ABSTRACT FROM AUTHOR]

Fungi have been identified as a prolific source of structurally unique secondary metabolites, many of which display promising biological and pharmacological properties. This review provides an overview of the structures of new natural products derived from fungi and their biological activities along with the research strategies, which focuses on literature published in the representative journals in 2023. In this review, a total of 553 natural products including 219 polyketides, 145 terpenoids, 35 steroids, 106 alkaloids, and 48 peptides are presented. By summarising the latest findings, this review aims to provide a guide and inspire further innovation in the fields of the discovery of fungal natural products and pharmaceutical development. [ABSTRACT FROM AUTHOR]

One novel polyketide, fusaritide A (1), was isolated from a marine fish-derived halotolerant fungal strain Fusarium verticillioide G102. The structure was determined through extensive spectroscopic analysis and high-resolution electrospray ionization mass spectrometry. Fusaritide A (1) with unprecedented structure reduced cholesterol uptake by inhibiting Niemann-Pick C1-Like 1 (NPC1L1). [ABSTRACT FROM AUTHOR]

The coastal region of the Caribbean is notable for the chemical diversity found in its sponge products, resulting in the biosynthesis of a range of natural marine products, including polyketides. The objective of this manuscript is to summarize the isolated polyketides from sponges of the genus Plakortis located around the Caribbean coasts. This review provides a comprehensive overview of specimen location, isolation procedures, characterization methods, and biological assay studies of about 95 polyketides isolated from 1978 to 2024 in the Caribbean coasts of The Bahamas, Cayman Islands, Belize, Dominica, Jamaica, Martinique, Panamá, Puerto Rico, and Tobago. The Caribbean polyketides have been isolated from different types of Plakortis sp., such as P. simplex, P. halichondroides, P. zyggompha, and P. angulospiculatus, which have demonstrated antimicrobial, anticancer, anti-inflammatory, antiparasitic, and antiviral activities. A variety of linear polyketides with different functionalities have been reported, including endoperoxides (1,2-dioxane), lactones, indane-type bicyclics (spiculane and zyggomphic), alcohols, alkenes, styryl groups, α,β-unsaturated carboxylic acids, and ketones, as well as related natural products of biosynthetic origin. The aim is to encourage further exploration by researchers in the Caribbean's coastal marine environments, promoting the discovery and investigation of novel polyketide cyclic peroxides and related secondary metabolites to identify additional bioactive medicinal natural products. [ABSTRACT FROM AUTHOR]

Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure‐activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post‐polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End‐16, which demonstrates significant potential for treating bladder cancer (BLCA). End‐16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End‐16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti‐BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties. [ABSTRACT FROM AUTHOR]

Modular polyketide synthases (PKSs) play a vital role in the biosynthesis of complex natural products with pharmaceutically relevant properties. Their modular architecture makes them an attractive target for engineering to produce platform chemicals and drugs. In this study, we demonstrate that the promiscuous malonyl/acetyl-transferase domain (MAT) from murine fatty acid synthase serves as a highly versatile tool for the production of polyketide analogs. We evaluate the relevance of the MAT domain using three modular PKSs; the short trimodular venemycin synthase (VEMS), as well as modules of the PKSs deoxyerythronolide B synthase (DEBS) and pikromycin synthase (PIKS) responsible for the production of the antibiotic precursors erythromycin and pikromycin. To assess the performance of the MAT-swapped PKSs, we analyze the protein quality and run engineered polyketide syntheses in vitro. Our experiments include the chemoenzymatic synthesis of fluorinated macrolactones. Our study showcases MAT-based reprogramming of polyketide biosynthesis as a facile option for the regioselective editing of substituents decorating the polyketide scaffold. Modular polyketide synthases (PKSs) play a vital role in the biosynthesis of complex natural products with pharmaceutically relevant properties, and their modular architecture makes them an attractive target for engineering to produce platform chemicals and drugs. In this study, the authors demonstrate that the promiscuous malonyl/acetyl-transferase domain (MAT) from murine fatty acid synthase serves as a highly versatile tool for the production of polyketide analogs. [ABSTRACT FROM AUTHOR]

Diaporthpyran A (1), diaporthester E (2) and diaporthester F (3), three new compounds along with four known compounds (4-7) were isolated from the crude extract of Diaporthe biguttusis T-24, an endophytic fungus isolated from Ligularia fischeri. The planar structures of compounds 1-3 including the relative and absolute configurations were elucidated on the basis of HRMS, NMR, J-based coupling constant analysis, CD, and calculated ECD analysis. In addition, compounds 1 and 3 were evaluated for their cytotoxic activities against four human cancer cell lines. [ABSTRACT FROM AUTHOR]

The biosynthetic pathway of actinorhodin in Streptomyces coelicolor A3(2) has been studied for decades as a model system of type II polyketide biosynthesis. The actinorhodin biosynthetic gene cluster includes a gene, actVI-orfA, that encodes a protein that belongs to the nuclear transport factor-2-like (NTF-2-like) superfamily. The function of this ActVI-ORFA protein has been a long-standing question in this field. Several hypothetical functions, including pyran ring cyclase, enzyme complex stability enhancer, and gene transcription regulator, have been proposed for ActVI-ORFA in previous studies. However, although the recent structural analysis of ActVI-ORFA revealed a solvent-accessible cavity, the protein displayed structural differences to the well-characterized cyclase SnoaL and did not possess a DNA-binding domain. The obtained crystal structure facilitates an inspection of the previous hypotheses regarding the function of ActVI-ORFA. In the present study, we investigated the effects of a series of actVI-orfA test plasmids with different mutations in an established vector/host system. Time-course analysis of dynamic metabolism profiles demonstrated that ActVI-ORFA prevented formation of shunt metabolites and may have a metabolic flux directing function, which shepherds the flux of unstable intermediates towards actinorhodin. The expression studies resulted in the isolation and structure elucidation of two new shunt metabolites from the actinorhodin pathway. Next, we utilized computational modeling to probe the active site of ActVI-ORFA and confirmed the importance of residues R76 and H78 in the flux directing functionality by expression studies. This is the first time such a function has been observed for a member of NTF-2-like superfamily in Streptomyces secondary metabolism. [ABSTRACT FROM AUTHOR]

Prymnesium parvum are harmful haptophyte algae that cause massive environmental fish kills. Their polyketide polyether toxins, the prymnesins, are among the largest nonpolymeric compounds in nature and have biosynthetic origins that have remained enigmatic for more than 40 years. In this work, we report the “PKZILLAs,” massive P. parvum polyketide synthase (PKS) genes that have evaded previous detection. PKZILLA-1 and -2 encode giant protein products of 4.7 and 3.2 megadaltons that have 140 and 99 enzyme domains. Their predicted polyene product matches the proposed pre-prymnesin precursor of the 90-carbon–backbone A-type prymnesins. We further characterize the variant PKZILLA-B1, which is responsible for the shorter B-type analog prymnesin-B1, from P. parvum RCC3426 and thus establish a general model of haptophyte polyether biosynthetic logic. This work expands expectations of genetic and enzymatic size limits in biology. [ABSTRACT FROM AUTHOR]

The development of new treatments for neglected tropical diseases (NTDs) remains a major challenge in the 21st century. In most cases, the available drugs are obsolete and have limitations in terms of efficacy and safety. The situation becomes even more complex when considering the low number of new chemical entities (NCEs) currently in use in advanced clinical trials for most of these diseases. Natural products (NPs) are valuable sources of hits and lead compounds with privileged scaffolds for the discovery of new bioactive molecules. Considering the relevance of biodiversity for drug discovery, a chemoinformatics analysis was conducted on a compound dataset of NPs with anti-trypanosomatid activity reported in 497 research articles from 2019 to 2024. Structures corresponding to different metabolic classes were identified, including terpenoids, benzoic acids, benzenoids, steroids, alkaloids, phenylpropanoids, peptides, flavonoids, polyketides, lignans, cytochalasins, and naphthoquinones. This unique collection of NPs occupies regions of the chemical space with drug-like properties that are relevant to anti-trypanosomatid drug discovery. The gathered information greatly enhanced our understanding of biologically relevant chemical classes, structural features, and physicochemical properties. These results can be useful in guiding future medicinal chemistry efforts for the development of NP-inspired NCEs to treat NTDs caused by trypanosomatid parasites. [ABSTRACT FROM AUTHOR]