Journal of Natural Products 最新文献

Linear long-chain hydrocarbons are common constituents of the outer cuticle of most insects. These cuticular hydrocarbons form the first barrier to the environment, preventing desiccation, but also play important roles in communication among many insects, transporting, for example, information on species, sex, or physiological state. Eueides is a genus of heliconiine butterflies, a group known for their complex mimicry systems. We report here the identification and synthesis of large macrocyclic lactones from the cuticles of five Eueides species, which largely replace the hydrocarbons. These lactones have chain lengths of 23-34 and ring sizes of 17-29. They occur in Eueides but not in other closely related genera such as Heliconius, Dryas, Dryadula, Agraulis, or Dione. Each species has a specific mixture of macrocyclic lactones. These unique bouquets may be used in species recognition, as visual cues may be unreliable in mimicry rings. We identified 43 different compounds using GC/MS, GC/IR, and enantioselective synthesis via ring-closing metathesis and Jacobsen hydrolytic kinetic resolution. The absolute configuration could not be determined because these lactones were not separable by gas chromatography on chiral phases.

Phomazaphilones A and B (1 and 2), azaphilones possessing a 5/6/6-fused tricyclic ring system, along with two known analogues, were discovered from the fungus Phomopsis sp. SCNU-F0049 was collected from the mangrove sediment. The structures were elucidated by extensive spectroscopic data and single-crystal X-ray diffraction. Phomazaphilone A (1) possesses a new 6,7,8,8a-tetrahydro-2H-furo[4,3,2-de]isoquinolin-2-one core, and phomazaphilone B (2) possesses a new 6,7,8,8a-tetrahydro-2H,5H-furo[4,3,2-de]isochromene-2,5-dione heterocyclic core. A possible biosynthetic pathway was proposed based on genome sequence analysis. Phomazaphilone B (2) inhibited NO production in LPS-stimulated RAW264.7 cells with an IC₅₀ value of 3.28 ± 0.24 μM and suppressed the expression levels of proinflammatory cytokines TNF-α and IL-6 in a dose-dependent manner without cytotoxicity.

Antimicrobial resistance represents an escalating global health crisis, with drug-resistant infections predicted to cause up to 10 million deaths annually by 2050, underscoring the urgent need for novel antibiotics. Natural products play a crucial role in the discovery and development of antibiotics, with myxobacteria emerging as a particularly promising source due to their ability to produce structurally diverse and bioactive compounds. One prominent example of antibiotics from myxobacteria are the sorangicins, potent inhibitors of the bacterial RNA polymerase (RNAP). Here, we report the isolation of two unprecedented compounds, neosorangicin A (1) and neosorangioside A (2), from Sorangium cellulosum strain Soce439, elucidated their molecular structures, thereby revealing significant structural variation in comparison to sorangicin, and describe their biosynthetic pathway. Neosorangicin A (1) exhibited strong activity against various Gram-positive bacteria, including potent effects against Mycobacterium tuberculosis and enhanced efficacy on intracellular Staphylococcus aureus. In a murine wound infection model, a head-to-head comparison of neosorangicin A (1) and sorangicin A (3) provided useful insights into how the altered physicochemical properties, arising from the shortened side chain and the lack of the free carboxylic acid of neosorangicin A, influence the in vivo efficacy of sorangicin derivatives.

Symbiosis, from Greek "living together" refers to the close association among organisms. Although these associations are found everywhere in nature, we do not know how these relationships are established or maintained over time. In this Perspective, we will focus on interorganism interactions involving microbes and eukaryotic hosts, particularly animals, plants, and humans, where symbiosis plays a critical role in health, development, and ecological fitness. We will focus on the chemical crosstalk between host and symbiont mediated by specialized small molecules. Finally, we suggest some steps for applying mass spectrometry-based metabolomic approaches to accelerate the understanding of these complex interactions.

Laboratory domestication of bacteria can negatively affect natural product production. This problem continues to plague discovery and development efforts. In this study, we investigated pladienolides from Streptomyces platensis, synthetic derivatives of which entered clinical trials for the treatment of acute myeloid leukemia. Solid cultures of the deposited S. platensis Mer-11107 yielded black, gray, and white colonies with identical 16S rRNA gene sequences, revealing that they were the same species. Importantly, metabolite analysis identified one white isolate with a 3-fold improvement in pladienolide B titers. Experimental evolution of black isolates gave rise to both gray and white colonies. In contrast, gray and white isolates did not generate the black phenotype, suggesting black isolates are ancestral strains and that the mechanism underlying the phenotypic heterogeneity is irreversible. Comparative genomics revealed sequence and structure variations that may help explain the observed differences in development and metabolite production. The increase in pladienolide titers with the white isolate is in line with the recent concept of division of labor within Streptomyces colonies, where genomic instability results in some cells specializing in antibiotic production and others remaining reproductive. Ultimately, identification of the pladienolide B overproducer will facilitate future studies in this important class of splice-modulating antitumor agents.

A cladiellin-type diterpene, 3-O-deacetylcladiellin (1), was isolated from the marine gastropod Ovula ovum, together with a known analogue 2. The NMR spectra of 1 and 2 exhibited unusually broad resonances. The structure and absolute configuration of 1 were unambiguously established by X-ray crystallographic analysis and electronic circular dichroism spectroscopy. DFT-based conformational analysis combined with variable-temperature NMR revealed that the NMR coalescence arises from conformational exchange of the flexible nine-membered ring. Chemical evidence suggests that 1 is likely derived from an unidentified soft coral prey of O. ovum. Compound 1 inhibits RANKL-induced osteoclast differentiation in RAW264 cells.

Vibrio anguillarum remains a major problem in marine aquaculture, motivating the search for ecologically grounded microbial strategies for pathogen control. We previously showed that a coculture of Vreelandella alkaliphila D2 and Sulfitobacter pontiacus D3, isolated from Isochrysis galbana, inhibited V. anguillarum more strongly than either strain alone. Here, we demonstrate that this suppression is driven by desferrioxamines (DFO) produced by V. alkaliphila, enabling synergistic iron sequestration through siderophore sharing with S. pontiacus. Mass spectrometry imaging revealed multiple DFO analogues spatially colocalized within inhibition zones and confirmed xenosiderophore uptake of DFO analogues by Sulfitobacter. Bioassays showed iron-chelation activity in V. alkaliphila, while iron supplementation and DFO-B standards validated siderophore-mediated bacteriostatic inhibition. Untargeted metabolomics found no increase in siderophore abundance in coculture, indicating that enhanced inhibition results from shared iron chelation rather than elevated production. Genome mining identified a complete DFO biosynthetic gene cluster in V. alkaliphila and a desferrioxamine receptor in Sulfitobacter. Finally, in axenic I. galbana, Sulfitobacter, alone or with Vreelandella, maintained V. anguillarum at the level of inoculation, highlighting that the substrate has a marked influence on inhibitory activity. Together, these findings show how DFOs act as shared public goods that enable both cooperation and pathogen antagonism.

Benzenediol lactones (BDL) and Monascus azaphilone pigments (MonAzP) are different classes of bioactive polyketides produced by distinct pathways. BDL are produced by highly reducing polyketide synthase (hrPKS) - nonreducing PKS (nrPKS) pairs where the starter acyl transferase (SAT) domain of the nrPKS recruits an advanced starter unit provided by the hrPKS. In contrast, the MonAzP nrPKS does not use a hrPKS partner: instead, its SAT domain selects acetyl-CoA as the priming unit. Here, we reconfigured the MonAzP nrPKS to collaborate in a dual-PKS system by replacing its SAT domain with that of a BDL nrPKS. This shifted the product spectrum from benzaldehydes to novel α-pyrones in the chimeric system. Our work highlights that SAT domain engineering may enforce noncognate hrPKS-nrPKS collaborations even for solitary nrPKSs. Nevertheless, the derailment of the native cyclization and product release routines indicates that domain compatibility must be considered when engineering to produce unnatural polyketides.

Ansamycins constitute a structurally distinctive class of macrolactams characterized by the 3-amino-5-hydroxybenzoic acid (AHBA) starter unit and a broad spectrum of pharmacological activities. Genome mining of the rhizosphere-derived Streptomyces sp. LR417 revealed a cryptic ansamycin biosynthetic gene cluster (pas) that remained transcriptionally silent under standard laboratory culture conditions. A combinatorial activation strategy, integrating the constitutive overexpression of pathway-specific positive regulators with AHBA precursor supplementation, successfully unlocked the biosynthetic potential of this cluster, affording 11 new pentaketide ansamycins, pannansamycins A-K (1-11). Compound 1 displayed potent radical-scavenging activity, while compounds 2 and 3 displayed moderate radical-scavenging and lipoxygenase inhibitory activities. These findings expand the structural diversity of the ansamycin family and provide new scaffolds with antioxidant potential worthy of further investigation.