A new fungal metabolite, nygerone A (), featuring a unique 1-phenylpyridin-4(1H)-one core that had previously not been reported from any natural source, has been obtained from Aspergillus niger using a chemical epigenetics methodology.

The recent investigation of a gene cluster encoding for a hybrid PKS-NRPS metabolite in the oral pathogen Streptococcus mutans UA159 yielded evidence that this natural product might play an important role regulating a range of stress tolerance factors. We have now characterized the major compound generated from this gene cluster, mutanobactin A, and demonstrated that this secondary metabolite is also capable of influencing the yeast-mycelium transition of Candida albicans.A complex suite of cross-species interactions are anticipated to occur among the wide range of microorganisms that constitute the human microbiome. 1-3 While a variety of compounds such as peptides, lipids, and acyl-homoserine lactones have emerged as key players in the multifarious exchanges among microbes and their hosts, 4,5 the important contributions of many other families of secondary metabolites have been largely overlooked. We reported that the deletion of a gene cluster encoding for a putative hybrid polyketide synthasenonribosomal peptide synthetase (PKS-NRPS) derived metabolite in the human oral pathogenic bacteria Streptococcus mutans UA159 resulted in a loss of several resistance traits associated with oxygen and hydrogen peroxide tolerance, as well as biofilm formation. 6 Given that a variety of secondary metabolites are excreted into the extracellular environment, we suspected that the biosynthetic products of this gene cluster (which we have dubbed the mutanobactins 6 ) may have additional yet undefined functions related to the interaction of S. mutans with other members of the oral microbiome. This hypothesis recently gained support based on co-culture studies in which mutanobactin-competent S. mutans and a mutanobactin deletion mutant strain (Δmub) were grown in the presence of Candida albicans. Whereas the mutanobactin producing strain of S. mutans was capable of maintaining C. albicans in a perpetual yeast morphological state (Fig. 1A), deletion of the mutanobactin cluster permitted C. albicans to shift into a mycelial growth pattern, which is believed to be the invasive form of the fungus (Fig. 1B). We now describe the distinctive † Electronic supplementary information (ESI) available: General methods, physical data, MS and NMR ( 1 H, 13 C, 1 H-1 H COSY, 1 H-1 H TOCSY, 1 H-1 H NOESY, 1 H-13 C HSQC, 1 H-13 C HMBC, and 1 H-15 N HMBC) for 1. Analytical-scale HPLC comparison of the crude extracts generated from wild-type S. mutans UA159 and Δmub strains grown on brain-heart-infusion agar plates enabled us to identify two metabolites in the elution profile that were present only in the wild-type organism. Scale-up fermentation of the wild-type strain was performed in a bioreactor with 15 L of brain-heart-infusion broth under microaerobic conditions at 37 °C to enable the isolation and structure characterization of the major metabolite. After 48 h, the cells and broth were partitioned against ethyl acetate and the solvent removed in vacuo. The resulting extract was resuspended in methanol and the organic soluble material ...

A review with 187 references, describing natural products that exhibit bioactive properties relevant to the treatment of protein aggregation-related neurodegenerative diseases (e.g., Huntington's, Parkinson's, and prion diseases) and comparing the chemical properties of these secondary metabolite leads to compounds in clinical use for treating central nervous system conditions.

Aberrant protein aggregation and misfolding are key pathological features of many neurodegenerative disorders, including Huntington's and Parkinson's diseases. Compounds that offer protection from toxicity associated with aggregation-prone neurodegenerative proteins may have applications for the treatment of a multitude of disorders. A high-throughput bioassay system with parallel electrospray ionization mass spectrometry screening has been designed for critical evaluation of milligram quantities of natural product extracts, including dietary substances, for compounds of pharmacological relevance to the treatment of human neurodegenerative diseases. Using Saccharomyces cerevisiae strains engineered to express mutant human huntingtin and alpha-synuclein, we are able to identify extracts and compounds that protect cells from toxicity associated with these proteins. Applying this screening paradigm, we determined that a bioactive green tea extract contains an assemblage of catechins that were individually characterized for their respective protective effects against huntingtin and alpha-synuclein toxicity.

Metabolomics is a powerful multi-parameter tool for evaluating phenotypic traits associated with disease processes. We have used 1H NMR metabolome profiling to characterize metabolic aberrations in a yeast model of Huntington's disease that are attributable to the mutant huntingtin protein's gain-of-toxic-function effects. A group of 11 metabolites (alanine, acetate, galactose, glutamine, glycerol, histidine, proline, succinate, threonine, trehalose, and valine) exhibited significant concentration changes in yeast expressing the N-terminal fragment of a mutant human huntingtin gene. Correspondence analysis was used to compare results from our yeast model to data reported from transgenic mice expressing a mutant huntingtin gene fragment and Huntington's disease patients. This technique enabled us to identify a variety of both model specific (pertaining to a single species) and conserved (observed in multiple species) biomarkers related to mutant huntingtin's toxicity. Among the 59 metabolites identified, four compounds (alanine, glutamine, glycerol, and valine) changed significantly in concentration in all three Huntington's disease systems. We propose that alanine, glutamine, glycerol, and valine should be considered as promising biomarkers for evaluating new Huntington's disease therapies, as well as providing unique insight into the mechanisms associated with mutant huntingtin toxicity.

There are tens of thousands of scientific papers about flavonoids and their impacts on human health. However, despite the vast amount of energy that has been put toward studying these compounds, a unified molecular mechanism that explains their bioactivity remains elusive. One contributing factor to the absence of a general mechanistic explanation of their bioactivity is the complexity of flavonoid chemistry in aqueous solutions at neutral pH. Flavonoids have acidic protons, are redox active, and frequently auto-oxidize to produce an array of degradation products including electrophilic quinones. Flavonoids are also known to interact with specificity and high affinity with a variety of proteins, and there is evidence that some of these interactions may be covalent. This review summarizes the mechanisms of flavonoid oxidation in aqueous solutions at neutral pH and proposes the formation of protein-flavonoid adducts or flavonoid-induced protein oxidation as putative mechanisms of flavonoid bioactivity in cells. Nucleophilic residues in proteins may be able to form covalent bonds with flavonoid quinones; alternatively, specific amino acid residues such as cysteine, methionine, or tyrosine in proteins could be oxidized by flavonoids. In either case, these protein-flavonoid interactions would likely occur at specific binding sites and the formation of these types of products could effectively explain how flavonoids modify proteins in cells to induce downstream biochemical and cellular changes.

We have investigated the in vitro antibacterial bioactivity of dichloromethane-soluble fractions of Artemisia californica, Trichostema lanatum, Salvia apiana, Sambucus nigra ssp. cerulea and Quercus agrifolia Née against a ΔtolC mutant strain of Escherichia coli. These plants are traditional medicinal plants of the Chumash American Indians of Southern California. Bioassay-guided fractionation led to the isolation of three flavonoid compounds from A. californica: jaceosidin (1), jaceidin (2), and chrysoplenol B (3). Compounds 1 and 2 exhibited antibacterial activity against E. coli ΔtolC in liquid cultures. The in vitro activity of 1 against the enoyl reductase enzyme (FabI) was measured using a spectrophotometric assay and found to completely inhibit FabI activity at a concentration of 100 μM. However, comparison of minimum inhibitory concentration values for 1-3 against E. coli ΔtolC and an equivalent strain containing a plasmid constitutively expressing fabI did not reveal any selectivity for FabI in vivo.

Exploration of a soft coral (Briareum sp.) from Vanuatu led to the isolation of three new briaranes, designated brialalepolides A (1), B (2), and C (3). Compounds 2 and 3 reduced the expression of COX-2 in human colon adenocarcinoma cells, as well as in murine macrophage cells. This is significant because the metabolic products of COX-2 have been implicated in the pathogenesis of colon cancer and other diseases.