Chrysosporazine C (1) is a fungal phenylpropanoid piperazine with potent P-glycoprotein inhibitory activity, yet its biosynthesis has remained elusive. Here, we identify the biosynthetic gene cluster cry for 1 and demonstrate that the Fe(II) and 2-oxoglutarate dependent (Fe/2OG) oxygenase Cry7 catalyzes an oxidative cyclization of chrysosporazine D (2) to form 1, thereby establishing its dihydroisoquinolone pharmacophore. Intriguingly, the homologous enzyme Hvm2 diverts the same substrate toward Z-selective desaturation to yield helvamide (3). Crystal structures of Cry7 and Hvm2 complexed with 2 and cofactors, combined with site-directed mutagenesis, reveal conserved overall folds but divergent active-site architectures that govern substrate orientation and chemoselectivity. MD simulations and QM/MM calculations predict that both enzymes initiate catalysis via Fe(IV)& boxH;O-mediated regioselective hydrogen atom transfer (HAT). Cry7 then likely proceeds through radical-mediated nucleophilic addition, followed by a secondary HAT mediated by a CO2-incorporated Fe(III)-bicarbonate species to enable aromatization. In contrast, Hvm2 probably employs a sequential HAT mechanism, utilizing Fe(III)-OH for a kinetically favored secondary HAT to achieve desaturation. These findings uncover the molecular logic by which homologous Fe/2OG oxygenases channel a shared intermediate into structurally and functionally distinct natural products, providing a framework for the rational engineering of Fe/2OG oxygenases.

An investigation into Australian pasture soil-derived microbes led to the prioritization of Streptomyces sp. S4S-00182A09 due to the media extract ability to inhibit the motility of dog heartworm Dirofilaria immitis microfilariae (Mf), and as a source of natural products with molecular formula unprecedented in the scientific literature. Fractionation of a scaled-up cultivation extract of S4S-00182A09 yielded the new terpenyl-p-aminobenzoic acids, craterstatins A-D (1-4), together with the known fatty acid, 2-hydroxy-12-methylmyristic acid (5). Structures were assigned to 1-5 on the basis of spectroscopic, ECD, and Marfey's analyses, as well as biosynthetic considerations and chemical transformation. Of note, craterstatin A (1) proved unstable to storage and handling, especially under acidic conditions, undergoing facile conversion to the stereoisomeric dehydration products craterstatins B (2) and C (3) that feature an unprecedented carbo-heterocyclic framework, with 3 undergoing quantitative conversion to 2 on storage. While the craterstatins 1-4 did not exhibit anthelmintic activity against D. immitis (EC50 > 100 μM), weak activity displayed by the hydroxylated fatty acid 5 prompted screening of a library of synthetic hydroxy fatty acids 6-11, which revealed modest inhibitory activity for (±)-3-hydroxyundecanoic acid (6), (±)-3-hydroxytetradecanoic acid (7), and (±)-3-hydroxypentadecanoic acid (8) (EC50 16.3, 28.2, and 19.0 μM, respectively).

A systematic chemical investigation of the deep-sea-derived fungus Penicillium limosum ZEN48 resulted in the isolation of four new indole-diketopiperazine alkaloids, limopiperazines A–D (1–4), alongside 16 known analogues (5–20). The structures of the new compounds were determined through comprehensive spectroscopic analysis, quantum chemical calculations, X-ray crystallography, and biogenetic considerations. Limopiperazine C (3) potently inhibited osteoclast differentiation and disrupted actin ring formation. Integrated RNA sequencing, RT-qPCR and molecular docking revealed that limopiperazine C exerts the anti-osteoclastogenic effect by modulating the ferroptosis signaling pathway via targeting heme oxygenase-1 (Hmox-1), positioning it as a promising lead compound for developing anti-osteoporotic agents.

Background/Objectives/Methods: A bioassay-informed investigation of the Australian pasture soil-derived Streptomyces sp. S4S-00193A39 yielded the anthelmintic principals as three new spiroketal polyketide alkaloids, goondoxazoles A-C (1-3), with structures assigned by detailed spectroscopic analysis. Results: A structure-activity relationship based on the ability to inhibit the motility of Dirofilaria immitis microfilariae (mf) revealed a positive correlation for the benzoxazole moiety present in 2 and 3 (EC50 55-85 nM) versus the ring-opened aminobenzoic acid moiety evident in 1 (EC50 1.38 µM). This hypothesis was strengthened by extension of the SAR assessment to the known benzoxazole natural products A-33583 (12), UK-1 (13) and nataxazole (14), and the new analogue 5-hydroxynataxazole (15), which were isolated in our lab from three additional Australian pasture soil-derived Streptomyces spp. Of note, while the benzoxazole methyl esters 13-15 exhibited approximately 9- to 65-fold lower potency against D. immitis mf compared with 2 and 3, the carboxylic acid substituted benzoxazole 12 displayed comparable activity (EC50 72 nM) against D. immitis mf, and >5-fold improved potency against D. immitis L4 larvae (EC50 0.43 µM). Conclusions: These observations reveal the promising anthelmintic potential (against D. immitis) for the new structurally complex and chiral goondoxazoles (e.g., 2 and 3), and demonstrate that this effect can be replicated, even improved, by simpler, achiral benzoxazole microbial natural products (e.g., 12).

Anthrasteroids were first encountered as acid rearrangement products of the fungal steroid ergosterol and then as geomarkers in deep-sea shale deposits, and while 3α-hydroxyanthrasteroids have been reported as fungal metabolites, 2β-hydroxyanthrasteroids remain rare. Our investigation of Australian soil-derived fungi yielded the 2β-hydroxyanthrasteroid pullenvasterols A-G (1-7), with structures assigned by spectroscopic and chemical analysis and biosynthetic considerations. Of note, 4 and 5 selectively inhibit the growth of coisolated fungi, suggestive of an ecological antifungal defense.

IntroductionScorpion venoms are natural sources of neurotoxins that primarily modulate the properties of neuronal ion channels, particularly voltage-gated sodium and potassium channels. However, they also contain a variety of small bioactive molecules that have been largely neglected in the omics era of toxinological research.MethodsIn the present study, we employed a high-throughput FLIPR screen of arthropod venoms against nicotinic acetylcholine receptors (nAChRs) expressed in the human SH-SY5Y neuroblastoma cell line. ResultsThe venom of the Malaysian forest scorpion Heterometrus spinifer (family: Scorpionidae) proved to be an agonist of nAChRs, and the small choline ester senecioylcholine was identified as being responsible for the observed effect. Synthetic senecioylcholine and its isomers tigloylcholine and angeloylcholine were not insecticidal when injected into sheep blowflies. DiscussionBased on previous reports of senecioylcholine being toxic to vertebrates along with the agonistic effect we observed on human nAChRs, we postulate that senecioylcholine in scorpion venom is likely to assist with vertebrate prey capture and defense against vertebrate predators. Since senecioylcholine has only been previously reported in marine gastropods and moths, its presence in scorpion venom seems to represent an unusual case of convergent evolution.

A detailed chemical investigation of the Australian pasture soil-derived Actinomadura sp. S4S-00069B10, utilizing optimized cultivation on four different solid-phase media (M1, IMA, D400, and YEME), yielded the new isoindolinone goondicones I-K (1-3) and anthra-γ-pyrone cratermycins A-D (4-7). Structures were assigned to 1-7 on the basis of detailed spectroscopic, ECD, and X-ray analyses as well as chemical transformations and biosynthetic considerations. The goondicones 1-3 are especially noteworthy in that they feature an unprecedented carbo-heterocyclic framework, with 1 and 2 undergoing a facile keto-enol-mediated equilibration to a 1:3 mixture (of C-13 epimers) that exhibits promising anthelmintic properties against the dog heartworm Dirofilaria immitis microfilariae (EC50 1.1 μM) and L4 larvae (EC50 1.3 μM). Notably, this activity is accompanied by measurable mammalian cytotoxicity, indicating a narrow therapeutic window. Together, these findings highlight the chemical novelty of Actinomadura-derived metabolites, and their value as structurally unique anthelmintics leads to further optimization.

Covering: January 2014-June 2025. Previous review: Natural Product Reports, 2014, 31, 1612Natural products (NPs) have long been foundational in medicine, from ancient herbal remedies to the discovery of transformative drugs like morphine and quinine. The mid-20th century marked a 'golden age' for antibiotic discovery from natural sources, which then expanded into other therapeutic areas. However, by the late 20th century, other technological advances had shifted NPs from being a central component of the discovery process to one of several options. This review explores the current role of NPs in pharmaceuticals by analysing NP-derived (NP-D) drugs approved since 2014 and clinical candidates in development as of the end of 2024. 58 NP-related drugs launched between January 2014 and June 2025 were identified, which included 45 NP and NP-D new chemical entities (NCEs) and 13 NP-antibody drug conjugates (NP-ADCs). Next, all 579 drugs-388 (67%) of which were NCEs and 191 (33%) were new biological entities (NBEs)-approved globally from 2014 to 2024 were analysed. In total, 56 (9.7%) of these 579 drugs were classified as NPs or NP-Ds using this review's NP definition: 44 NCEs (7.6% overall; 11.3% of NCEs) and 12 NP-ADCs (2.1% overall; 6.3% of NBEs). The number of new NP-D NCEs and NP-ADCs has fluctuated between 0 and 8 annually since 2014, with an average of five approvals per year. Next, 125 NP and NP-D compounds were identified that were undergoing clinical trials or in the registration phase at the end of December 2024. Thirty-three new pharmacophores not previously found in approved drugs are now in development; however, only one has been discovered in the past 15 years. This review highlights the enduring promise of NPs, despite their diminished role in drug discovery, and advocates for renewed emphasis on bioassay-guided isolation and mode of action studies to identify new drug leads.

Covering literature to September 2025This review provides a comprehensive account of the 217 natural product inspired antibiotics that have been approved for human use from 1943 through to September 2025, inclusive of 52 (24%) that are natural products (NPs) and 165 (76%) that are semi-synthetic or synthetic derivatives of natural products (NP-Ds). These are organized into sixteen categories defined by shared structural motifs and, in many cases, common mechanisms of action. Each antibiotic is classified as either a NP or NP-D, annotated by a molecular structure that, where relevant, highlights the relationships between NPs and NP-Ds. Market details are also provided, including the company that brought each antibiotic to market, the year and country of first approval, the spectrum of usage across pathogen classes, routes of administration, current status, and selected commentary on mechanisms of action. The assembled dataset is further analysed through a series of charts that illustrate insightful trends that document the remarkable history and lasting impact of NP inspired antibiotics. The review concludes with observations on the historic impact and future prospects of natural products as a source of inspiration for the development of new generations of antibiotics.

Seven new sesquiterpene hydroquinone/quinone (SQ) meroterpenoids, cinerols L-R (1-7), along with four known analogues (8-11), were identified from a marine sponge, Dysidea cinerea, collected from the shore of the Xisha Islands in the South China Sea. The structures of 1-7 were established by the analysis of NMR, high-resolution MS, and comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Cinerol L (1) is particularly noteworthy, as it features a 5H-pyrrolo[1,2a]-benzimidazole moiety modified by an ethyl sulfonate, while cinerols N (3) and O (4) possess a unique acetyl-substituted hydroquinone moiety. Cinerols L-R (1-7) were evaluated for their inhibitory activity against inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and prostaglandin E2 (PGE2) with IC50 values of 5-20 μM in lipopolysaccharide (LPS)-induced RAW 264.7 mouse macrophages. Furthermore, the potent inhibitory activity on inflammatory cytokines of 4 prompted us to evaluate its effect on the nuclear factor-κB (NF-κB)/mitogen-activated protein kinase (MAPK) signaling pathway, a critical pathway that contributes to the inflammatory responses. Cinerol O (4) was unveiled to inhibit cyclooxygenase-2 (COX-2) expression and the production of inflammatory cytokines via suppressing the expression of NF-κB and MAPKs in LPS-induced RAW 264.7 macrophages.

A bromotropone corresponding to the agylcone of the glycosylated sesquiterpenoid natural product liriosmaside A has been prepared over ten steps and in a fully regio-controlled manner through the gem-dibromocyclopropane-mediated ring-expansion of a readily accessible decalenone. A Pd[0]-mediated glucosylation reaction applied to this bromotropone afforded a product mixture from which an enantiomerically pure cross-coupling product could be obtained and its structure confirmed through single-crystal X-ray analysis of a derivative. Various (unsuccessful) attempts are described to selectively acylate the last compound and thereby install the 3-hydroxy-3-methylglutaric acid or HMGA-containing side chain of the title natural product. A literature survey of other natural products embodying the HMGA motif suggest that liriosmaside A and its co-metabolite liriosmaside B could be S-configured at C3". The evaluation of the glucosylated tropone in a series of anti-bacterial, anti-fungal and cytotoxicity assays reveals that it is inactive in all of these and so emphasizing the prospect that this and related troponoids, including the natural products liriosmaside A and B, can serve as useful models for new anti-viral agents.

The MATRIX protocol presents a novel miniaturized 24-well plate approach for microbial cultivation profiling, enabling the efficient and parallel assessment of microbial metabolite production. This method integrates a media MATRIX within a microbioreactor to facilitate the creation of diverse growth conditions for microbial cultivation. The 24-well format supports the simultaneous study of multiple microbial strains and conditions, allowing the discovery of novel bioactive compounds. By employing a variety of media compositions and cultivations, MATRIX enhances the understanding of microbial metabolic pathways and interactions. This protocol provides a robust platform for natural product discovery, microbial ecology studies, and drug development, showcasing its potential to uncover new natural products and other valuable bioactives. The MATRIX approach offers a resource-efficient platform for microbial biodiscovery, contributing significantly to natural product research and drug development.

This chapter reports the successful synthesis of talarolide A (1), a natural product exhibiting a unique hydroxamate H-bond bridge, through a carefully designed solid-phase approach. By systematically selecting the disconnection site, we synthesized a protected linear precursor, which was then sequentially deprotected and cyclized. We discovered that the order of deprotection and cyclization was critical: precyclization of the unprotected peptide facilitated the correct conformational folding essential for achieving the natural product's structure. This approach not only yielded talarolide A but also revealed a noncanonical atropisomer (atrop-talarolide A 5), providing new insights into the role of hydroxamate H-bond bridging in atropisomerism among nonribosomal peptide synthetase (NRPS)-derived cyclic peptides.

Investigation of the secondary metabolites of Streptomyces virginiae CMB-CA091 isolated from the quartz-rich (tepui) soil of a cave in Venezuela yielded two new dimeric phenazine glycosides, tepuazines A and B (1 and 2); three new monomeric phenazine glycosides, tepuazines C-E (3-5); and a series of known analogues, baraphenazine G (6), phenazinolin D (7), izumiphenazine C (8), 4-methylaminobenzoyl-l-rhamnopyranoside (9), and 2-acetamidophenol (10). Structures were assigned to 1-10 on the basis of detailed spectroscopic analysis and biosynthetic considerations, with 1 and 2 featuring a rare 2-oxabicyclo[3.3.1]nonane-like ring C/D bridge shared with only a handful of known Streptomyces natural products. We propose a plausible convergent biosynthetic relationship linking all known members of this structure class that provides a rationale for the observed ring C/D configuration.

Subjecting the Australian marine-derived fungus Aspergillus noonimiae CMB-M0339 to cultivation profiling using an innovative miniaturized 24-well plate format (MATRIX) enabled access to new examples of the rare class of 2,6-diketopiperazines, noonazines A–C (1–3), along with the known analogue coelomycin (4), as well as a new azaphilone, noonaphilone A (5). Structures were assigned to 1–5 on the basis of a detailed spectroscopic analysis, and in the case of 1–2, an X-ray crystallographic analysis. Plausible biosynthetic pathways are proposed for 1–4, involving oxidative Schiff base coupling/dimerization of a putative Phe precursor. Of note, 2 incorporates a rare meta-Tyr motif, typically only reported in a limited array of Streptomyces metabolites. Similarly, a plausible biosynthetic pathway is proposed for 5, highlighting a single point for stereo-divergence that allows for the biosynthesis of alternate antipodes, for example, the 7R noonaphilone A (5) versus the 7S deflectin 1a (6).

Subunit vaccines require an immunostimulant (adjuvant) and/or delivery system to induce immunity. However, currently, available adjuvants are either too dangerous in terms of side effects for human use (experimental adjuvants) or have limited efficacy and applicability. In this study, we examined the capacity of mannose-lipopeptide ligands to enhance the immunogenicity of a vaccine consisting of polyleucine(L15)-antigen conjugates anchored to liposomes. The clinically tested Group A Streptococcus (GAS) B-cell epitope, J8, combined with universal T helper PADRE (P) was used as the antigen. Six distinct mannose ligands were incorporated into neutral liposomes carrying L15PJ8. While induced antibody titers were relatively low, the ligand carrying mannose, glycine/lysine spacer, and two palmitic acids as liposomal membrane anchoring moieties (ligand 3), induced significantly higher IgG titers than non-mannosylated liposomes. The IgG titers were significantly enhanced when positively charged liposomes were employed. Importantly, the produced antibodies were able to kill GAS bacteria. Unexpectedly, the physical mixture of only ligand 3 and PJ8 produced self-assembled nanorods that induced antibody titers as high as those elicited by the lead liposomal formulation and antigen adjuvanted with the potent, but toxic, complete Freund’s adjuvant (CFA). Antibodies produced upon immunization with PJ8 + 3 were even more opsonic than those induced by CFA + PJ8. Importantly, in contrast to CFA, ligand 3 did not induce observable adverse reactions or excessive inflammatory responses. Thus, we demonstrated that a mannose ligand, alone, can serve as an effective vaccine nanoadjuvant.

Chemical profiling of soil-derived microbes collected under the auspices of the Australian citizen science initiative Soils for Science detected two fungi, Clonostachys sp. S4S-07771A07 and Coccidiodes sp. S4S-14879B01, capable of producing pullenvalenes, a rare class of triterpene glycoside. Cultivation profiling followed by scaled up cultivation and fractionation of the former yielded the known pullenvalenes A-D (1-4) and the new analogues E-H (5-8), with structures secured by detailed spectroscopic analysis and biogenetic considerations. This study reveals that the pullenvalenes 1-8 are produced by several genera of fungi (Clonostachys, Coccidiodes and Talaromyces) recovered from different geographic locations and substrates. We also draw attention to structural and biosynthetic similarities with the known Red Sea sponge metabolites neviotines A-D (9-12) and abudinols A-B (13-14), prompting speculation that the latter may be products of sponge-associated fungi.

Two novel meroterpenoids, alliisativins A and B (1, 2) were discovered through a genome-based exploration of the biosynthetic gene clusters of the deep-sea-derived fungus Penicillium allii-sativi MCCC entry 3A00580. Extensive spectroscopic analysis, quantum calculations, chemical derivatization, and biogenetic considerations were utilized to establish their structures. Alliisativins A and B (1, 2) possess a unique carbon skeleton featuring a drimane sesquiterpene with a highly oxidized polyketide. Noteworthily, alliisativin A (1) showed dual activity in promoting osteogenesis and inhibiting osteoclast, indicating an antiosteoporosis potential.

Background/Objectives: There is an urgent need for new and improved anthelmintics that are not constrained by existing resistance pathways and that can safeguard the health and welfare of animals. Methods: An integrated platform of chemical, bioassay, and cultivation profiling applied to a library of microbes isolated from Australian livestock pasture soil was used to detect and guide the production, isolation, characterization, identification, and evaluation of new natural products with anthelmintic properties. Results: A global natural products social (GNPS) molecular network analysis of 110 Australian pasture-soil-derived microbial extracts prioritized for antiparasitic activity identified unique molecular families in the extract of Streptomyces sp. S4S-00185A06, a strain selectively active against Dirofilaria immitis microfilariae. UPLC-DAD analysis identified metabolites with unique UV-vis chromophores and unprecedented molecular formulas. A chemical investigation of Streptomyces sp. S4S-00185A06 yielded goondicones A–H (1–8) as new examples of a rare class of spiro-isoindolinones, with structures assigned on the basis of detailed spectroscopic analysis, ECD calculations, and biosynthetic considerations. Conclusions: While goondicones 1–8 exhibit little to no in vitro inhibitory activity against Gram-positive, Gram-negative, and/or fungal pathogens, human carcinoma cells, or the livestock gastrointestinal parasite Haemonchus contortus L1–L3 larvae, 5 and 6 (and, to a lesser extent, 1) inhibit the motility of heartworm Dirofilaria immitis microfilaria (IC50 10–11 μM). A structure activity relationship analysis based on the co-metabolites 1–8 suggests that (i) an 8-OH is preferable to 8–oxo moiety, (ii) 20-NMe and 3-OH moieties are essential, and (iii) C-9 epimerization exerts no discernible impact on in vitro potency.