Spithioneines A and B (1 and 2), two new bohemamine-type pyrrolizidine alkaloids possessing an unusual ergothioneine moiety, were isolated from a marine-derived Streptomyces spinoverrucosus. Their ...structures were elucidated by spectroscopic analysis, CD spectra, and chemical degradation and synthesis. Compounds 1 and 2 are rare natural products that incorporate the amino acid ergothioneine.
Thiasporine A (1), the first natural product with a 5-hydroxy-4H-1,3-thiazin-4-one moiety, along with two new thiazole derivatives, thiasporines B and C (2 and 3), were isolated from the ...marine-derived Actinomycetospora chlora SNC-032. The structures of 1–3 were established on the basis of comprehensive spectroscopic analysis and chemical methods. Thiasporine A showed cytotoxicity against the non-small-cell lung cancer cell line H2122 with an IC50 value of 5.4 μM.
The gut-brain axis is crucial to microbial-host interactions. The neurotransmitter serotonin is primarily synthesized in the gastrointestinal (GI) tract, where it is secreted into the lumen and ...subsequently removed by the serotonin transporter, SERT. Here, we show that serotonin decreases virulence gene expression by enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium, a murine model for EHEC. The membrane-bound histidine sensor kinase, CpxA, is a bacterial serotonin receptor. Serotonin induces dephosphorylation of CpxA, which inactivates the transcriptional factor CpxR controlling expression of virulence genes, notably those within the locus of enterocyte effacement (LEE). Increasing intestinal serotonin by genetically or pharmacologically inhibiting SERT decreases LEE expression and reduces C. rodentium loads. Conversely, inhibiting serotonin synthesis increases pathogenesis and decreases host survival. As other enteric bacteria contain CpxA, this signal exploitation may be engaged by other pathogens. Additionally, repurposing serotonin agonists to inhibit CpxA may represent a potential therapeutic intervention for enteric bacteria.
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•Enterohemorrhagic E. coli (EHEC) and C. rodentium sense serotonin in the gut•Bacterial CpxA acts as a serotonin sensor•Serotonin decreases virulence of EHEC in vitro and C. rodentium during murine infection•Genetic and pharmacological changes in gut serotonin modulate C. rodentium disease
Kumar, Russell et al. demonstrate that changes in intestinal serotonin levels alter the pathogenesis of enteric bacteria. Serotonin decreases the expression of bacterial virulence genes by signaling through the bacterial histidine sensor kinase CpxA. Genetic or pharmacological enhancement of intestinal serotonin levels reduces bacterial loads and enhances host survival.
Two new 1,3-oxazin-6-one derivatives (1 and 2) and six new bohemamine-type pyrrolizidine alkaloids (3–8) were isolated from the marine-derived Streptomyces spinoverrucosus strain SNB-048. Their ...structures including the absolute configurations were fully elucidated on the basis of spectroscopic analysis, ECD spectra, quantum chemical calculations, and chemical methods. Compounds 1 and 2 possess a γ-lactam moiety and a 1,3-oxazin-6-one system.
Drugs that mirror the cellular effects of starvation mimics are considered promising therapeutics for common metabolic disorders, such as obesity, liver steatosis, and for ageing. Starvation, or ...caloric restriction, is known to activate the transcription factor EB (TFEB), a master regulator of lipid metabolism and lysosomal biogenesis and function. Here, we report a nanotechnology-enabled high-throughput screen to identify small-molecule agonists of TFEB and discover three novel compounds that promote autophagolysosomal activity. The three lead compounds include the clinically approved drug, digoxin; the marine-derived natural product, ikarugamycin; and the synthetic compound, alexidine dihydrochloride, which is known to act on a mitochondrial target. Mode of action studies reveal that these compounds activate TFEB via three distinct Ca
-dependent mechanisms. Formulation of these compounds in liver-tropic biodegradable, biocompatible nanoparticles confers hepatoprotection against diet-induced steatosis in murine models and extends lifespan of Caenorhabditis elegans. These results support the therapeutic potential of small-molecule TFEB activators for the treatment of metabolic and age-related disorders.
Chemical examination of an extract from an Erythrobacter sp. isolated from mangrove sediments yielded erythrazoles A (1) and B (2). The erythrazoles are of mixed biosynthetic origin containing a ...tetrasubstituted benzothiazole, an appended diterpene side chain, and a glycine unit. Erythrazole B is cytotoxic to a panel of non-small cell lung cancer (NSCLC) cell lines, with IC50 values of 1.5, 2.5, and 6.8 μM against H1325, H2122, and HCC366, respectively.
Biosynthetic mechanisms of natural products primarily depend on systems of protein catalysts. However, within the field of biosynthesis, there are cases in which the inherent chemical reactivity of ...metabolic intermediates and substrates evades the involvement of enzymes. These reactions are difficult to characterize based on their reactivity and occlusion within the milieu of the cellular environment. As we continue to build a strong foundation for how microbes and higher organisms produce natural products, therein lies a need for understanding how protein independent or nonenzymatic biosynthetic steps can occur. We have classified such reactions into four categories: intramolecular, multicomponent, tailoring, and light-induced reactions. Intramolecular reactions is one of the most well studied in the context of biomimetic synthesis, consisting of cyclizations and cycloadditions due to the innate reactivity of the intermediates. There are two subclasses that make up multicomponent reactions, one being homologous multicomponent reactions which results in dimeric and pseudodimeric natural products, and the other being heterologous multicomponent reactions, where two or more precursors from independent biosynthetic pathways undergo a variety of reactions to produce the mature natural product. The third type of reaction discussed are tailoring reactions, where postmodifications occur on the natural products after the biosynthetic machinery is completed. The last category consists of light-induced reactions involving ecologically relevant UV light rather than high intensity UV irradiation that is traditionally used in synthetic chemistry. This review will cover recent nonenzymatic biosynthetic mechanisms and include sources for those reviewed previously.
Inducamides A–C (1–3), three new chlorinated alkaloids featuring an amide skeleton generated by a tryptophan fragment and a 6-methylsalicylic acid unit, were isolated from a chemically induced mutant ...strain of Streptomyces sp. with the inducamides only being produced in the mutant strain. Their structures, including stereochemistry, were determined by spectroscopic analysis, Marfey’s method, and CD spectroscopy.
Discoipyrroles A–D (DPA–DPD) are recently discovered natural products produced by the marine bacterium Bacillus hunanensis that exhibit anticancer properties in vitro. Initial biosynthetic studies ...demonstrated that DPA is formed in the liquid fermentation medium of B. hunanensis from three secreted metabolites through an unknown but protein-independent mechanism. The increased identification of natural products that depend on non-enzymatic steps creates a significant need to understand how these different reactions can occur. In this work, we utilized 15N-labeled starting materials and continuous high-sensitivity 1H–15N HMBC NMR spectroscopy to resolve scarce reaction intermediates of the non-enzymatic discoipyrrole reaction as they formed in real time. This information guided supplemental experiments using 13C- and 18O-labeled materials to elucidate the details of DPA’s non-enzymatic biosynthesis, which features a highly concerted pyrrole formation and necessary O2-mediated oxidation. We have illustrated a novel way of using isotopically enhanced two-dimensional NMR spectroscopy to interrogate reaction mechanisms as they occur. In addition, these findings add to our growing knowledge of how multicomponent non-enzymatic reactions can occur through inherently reactive bacterial metabolites.
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