Microbial gatekeepers: unraveling the role of the gut microbiota enzyme DPP4 in diabetes management.

Wang et al. identified dipeptidyl peptidase 4 (DPP4) as a gut microbe-derived enzyme that impacts on host glucose metabolism. They further introduced a novel therapeutic, daurisoline-d4 (Dau-d4), a selective microbial DPP4 (mDPP4) inhibitor that shows promise in improving glucose tolerance, highlighting the potential of therapies that target both host enzymes and gut microbial enzymes.

Concise Biosynthesis of Tropone-Containing Spiromaterpenes by a Sesquiterpene Cyclase and a Multifunctional P450 from a Deep-Sea-Derived Spiromastix sp. Fungus.

Spiromaterpenes are a group of rare tropone-containing sesquiterpenes with antineuroinflammatory activity. Herein, we elucidate their biosynthetic pathway in a deep-sea-derived Spiromastix sp. fungus by heterologous expression, biochemical characterization, and incubation experiments. The sesquiterpene cyclase SptA was first characterized to catalyze the production of guaia-1(5),6-diene, and a multifunctional cytochrome P450 catalyzed the tropone ring formation. These results provide important clues for the rational mining of bioactive guaiane-type sesquiterpenes and expand the repertoire of P450 activities to synthesize unique building blocks of natural products.

Genome mining as a biotechnological tool for the discovery of novel marine natural products.

Compared to terrestrial environments, the oceans harbor a variety of environments, creating higher biodiversity, which gives marine natural products a high occurrence of significant biology and novel chemistry. However, traditional bioassay-guided isolation and purification strategies are severely limiting the discovery of additional novel natural products from the ocean. With an increasing number of marine microorganisms being sequenced, genome mining is gradually becoming a powerful tool to retrieve novel marine natural products. In this review, we have summarized genome mining approaches used to analyze key enzymes of biosynthetic pathways and predict the chemical structure of new gene clusters by introducing successful stories that used genome mining strategy to identify new marine-derived compounds. Furthermore, we also put forward challenges for genome mining techniques and their proposed solutions. The detailed analysis of the genome mining strategy will help researchers to understand this novel technique and its application. With the development of a genome sequence, genome mining strategies will be applied more widely, which will drive rapid development in the field of marine natural product development.

Discovery of Three New Phytotoxins from the Fungus Aspergillus nidulans by Pathway Inactivation.

Fungi are a source of novel phytotoxic compounds to be explored in the search for effective and environmentally safe herbicides. The genetic inactivation of the biosynthetic pathway of the new phytotoxin cichorine has led to the isolation of three novel phytotoxins from the fungus Aspergillus nidulans: 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6). The structure of the new compounds was clearly determined by a combination of nuclear magnetic resonance (NMR) analysis and high-resolution electrospray ionization (HRESIMS). The phytotoxic bioassay was studied on leaves from Zea mays and Medicago polymorpha L. at the concentration of 5 × 10-3 M by using a moist chamber technique. Novel phytotoxins 8-methoxycichorine (4), 8-epi-methoxycichorine (5), and N-(4'-carboxybutyl) cichorine (6) exhibited a better phytotoxic effect than cichorine.

Chemistry and Biology of Teixobactin.

Bacterial resistance to existing drugs is becoming a serious public health issue, urging extensive search for new antibiotics. Teixobactin, a cyclic depsipeptide discovered in a screen of uncultured bacteria, shows potent activity against all the tested Gram-positive bacteria. Remarkably, no teixobactin-resistant bacterial strain has been obtained despite extensive efforts, highlighting the great potential of teixobactin as a lead compound in the fight against antimicrobial resistance (AMR). This review summarizes recent progresses in the understanding of many aspects of teixobactin, including chemical structure, biological activity, biosynthetic pathway, and mode of action. We also discuss the different synthetic strategies in producing teixobactin and its analogues, and the structure-activity relationship (SAR) studies.

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes.

Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N(5)-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.

Regulation of antimicrobial activity and xenocoumacins biosynthesis by pH in Xenorhabdus nematophila.

BACKGROUND: Xenocoumacin 1 (Xcn1) and Xenocoumacin 2 (Xcn2) are the main antimicrobial compounds produced by Xenorhabdus nematophila. Culture conditions, including pH, had remarkably distinct effects on the antimicrobial activity of X. nematophila. However, the regulatory mechanism of pH on the antimicrobial activity and antibiotic production of this bacterium is still lacking. RESULTS: With the increase of initial pH, the antimicrobial activity of X. nematophila YL001 was improved. The levels of Xcn1 and nematophin at pH 8.5 were significantly (P < 0.05) higher than that at pH 5.5 and 7.0. In addition, the expression of xcnA-L, which are responsible for the production of Xcn1 was increased and the expression of xcnMN, which are required for the conversion of Xcn1 to Xcn2 was reduced at pH 8.5. Also, the expression of ompR and cpxR were decreased at pH 8.5. CONCLUSION: The alkaline pH environment was found to be beneficial for the production of Xcn1 and nematophin, which in turn led to high antimicrobial activity of X. nematophila at pH 8.5.

[Association of SPO11 and GST gene polymorphisms with idiopathic male infertility in ethnic Han Chinese].

OBJECTIVE: To explore the possible roles of polymorphisms of SPO11 and glutathionine S-transferase (GST) genes in idiopathic male infertility in a ethnic Han Chinese population from Henan. METHODS: Multiplex PCR and DNA sequencing were performed to determine the SPO11 c.517C>T(rs28368082) and GST genes (GSTM1, GSTT1, GSTP1) polymorphisms in 216 idiopathic male infertility cases and 198 normal samples. RESULTS: The frequencies of the SPO11 CC and CT genotypes were 87.5% (189/216) and 12.5% (27/216) in the patients, and 97.5% (193/198) and 2.5% (5/198) in the controls, respectively. The frequencies of SPO11 CC and CT genotypes, the A>G transition at nucleotide 313 in the exon 5 of the GSTP1 gene, and the frequencies of combined genotypes GSTM1 (-/-), GSTT1 (+/+), GSTP1 (AA) and SPO11 (CT) were significantly different between the two groups (P<0.05). CONCLUSION: The rs28368082 polymorphism of the SPO11 gene, the A>G transition at nucleotide 313 in the exon 5 of the GSTP1 gene, and the combined genotypes of GSTM1 (-/-), GSTT1 (+/+), GSTP1 (AA) and SPO11 (CT) may be associated with idiopathic male infertility in ethnic Han Chinese.

[Study on Archaeological Lime Powders from Taosi and Yinxu Sites by FTIR].

Archaeological lime powders samples from Taosi and Yinxu sites, natural limestone and experimentally prepared lime mortar were investigated by means of Fourier transform infrared spectrometry (FTIR) to identify the raw material of lime powders from Taosi and Yinxu sites. Results show that ν2/ν4 ratio of calcite resulted from carbonation reaction of man-made lime is around 6.31, which is higher than that of calcite in natural limestone and reflects the difference in the disorder of calcite crystal structure among the natural limestone and prepared lime mortar. With additional grinding, the values of v2 and ν4 in natural limestone and prepared lime mortar decrease. Meanwhile, the trend lines of ν2 versus ν4 for calcite in experimentally prepared lime mortar have a steeper slope when compared to calcite in natural limestone. These imply that ν2/ν4 ratio and the slope of the trend lines of ν2 versus ν4 can be used to determine the archaeological man-made lime. Based on the experiment results, it is possible that the archaeological lime powder from Taosi and Yinxu sites was prepared using man-made lime and the ancient Chinese have mastered the calcining technology of man-made lime in the late Neolithic period about 4 300 years ago.

Use of a phosphonate methyltransferase in the identification of the fosfazinomycin biosynthetic gene cluster.

Natural product discovery has been boosted by genome mining approaches, but compound purification is often still challenging. We report an enzymatic strategy for "stable isotope labeling of phosphonates in extract" (SILPE) that facilitates their purification. We used the phosphonate methyltransferase DhpI involved in dehydrophos biosynthesis to methylate a variety of phosphonate natural products in crude spent medium with a mixture of labeled and unlabeled S-adenosyl methionine. Mass-guided fractionation then allowed straightforward purification. We illustrate its utility by purifying a phosphonate that led to the identification of the fosfazinomycin biosynthetic gene cluster. This unusual natural product contains a hydrazide linker between a carboxylic acid and a phosphonic acid. Bioinformatic analysis of the gene cluster provides insights into how such a structure might be assembled.

The gut-Snhg9 interplay as a new path to metabolic health.

Parsing the intricate interplay between gut microbiota, gene modulation, and host metabolism remains challenging. Wang et al. employed diverse methods to uncover how the gut microbiota reshapes intestinal lipid metabolism through the lncRNA Snhg9, underscoring the value of systems biology approaches in dissecting host-microbiome relationships involved in metabolic disorders.

Genomics refined: AI-powered perspectives on structural analysis.

Understanding protein function by deciphering 3D structure has distinct limitations. A recent study by Huang et al. used AlphaFold2, an artificial intelligence (AI) protein-folding prediction model, to predict and classify deaminase proteins based on structural similarities, highlighting the untapped potential of AI in functional genomics and protein engineering.

Clinical crusade: zosurabalpin's charge against antibiotic resistance.

In a recent report, Zampaloni et al. describe a novel tethered macrocyclic peptide (MCP) antibiotic, zosurabalpin, that disrupts the essential function of the LptB2FGC complex in Gram-negative bacteria and demonstrates efficacy against carbapenem-resistant Acinetobacter baumannii (CRAB). Its preclinical success suggests a substantial shift in treating antibiotic resistance, pending clinical trials to validate its effectiveness, pharmacokinetics, and resistance management.

Exploring the antibiotic potential of cultured 'unculturable' bacteria.

In response to the severe global antibiotic resistance crisis, this forum delves into 'unculturable' bacteria, believed to be a promising source of novel antibiotics. We propose remarkable drug discovery strategies that leverage these bacteria's diversity, aspiring to transform resistance management. The urgent call for new antibiotics accentuates the essentiality of further research.

3-O-acylated bile acids: disrupters or harmonizers of metabolism?

Unveiling a metabolic mystery, this article explores how 3-O-acylated bile acids, specifically 3-O-succinylated cholic acid (3-sucCA) and 3-acetylated cholic acid (3-acetyCA), modified by gut microbes Bacteroides uniformis and Christensenella minuta, respectively, may either disrupt or harmonize our metabolic processes, offering novel therapeutic avenues for conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2D).

Biosafety and biosecurity: treading China's synbio tightrope.

Our second piece dissects China's intricate balancing act in synthetic biology (synbio), analyzing its adept maneuvering between fostering innovation and imposing strict regulations. The priority is enhancing biosecurity, biosafety, and public trust, crucial for sustainable gene editing advancements and preventing potential misuse of synthetic viruses.

Intellectual property and funding: fueling Chinese synbio.

As China emerges as a synthetic biology (synbio) global leader, it faces distinct science-society challenges. Our series offers a snapshot of China's synbio state, emphasizing the intersection and its policy implications. The debut piece elucidates the intellectual property rights (IPR)-funding interplay in China's expanding synbio territory, underlining its key role in driving innovation and commercialization.

Enhancing the yield of Xenocoumacin 1 in Xenorhabdus nematophila YL001 by optimizing the fermentation process.

Xenocoumacin 1 (Xcn 1), antibiotic discovered from secondary metabolites of Xenorhabdus nematophila, had the potential to develop into a new pesticide due to its excellent activity against bacteria, oomycetes and fungi. However, the current low yield of Xcn1 limits its development and utilization. To improve the yield of Xcn1, response surface methodology was used to determine the optimal composition of fermentation medium and one factor at a time approach was utilized to optimize the fermentation process. The optimal medium composed of in g/L: proteose peptone 20.8; maltose 12.74; K2HPO4 3.77. The optimal fermentation conditions were that 25 °C, initial pH 7.0, inoculum size 10%, culture medium 75 mL in a 250 mL shake flask with an agitation rate of 150 rpm for 48 h. Xenorhabdus nematophila YL001 was produced the highest Xcn1 yield (173.99 mg/L) when arginine was added to the broth with 3 mmol/L at the 12th h. Compared with Tryptic Soy Broth medium, the optimized fermentation process resulted in a 243.38% increase in Xcn1 production. The obtained results confirmed that optimizing fermentation technology led to an increase in Xcn1 yield. This work would be helpful for efficient Xcn1 production and lay a foundation for its industrial production.

Neocosmospora sp.-derived resorcylic acid lactones with in vitro binding affinity for human opioid and cannabinoid receptors.

Bioassay-guided fractionation of a fungus Neocosmospora sp. (UM-031509) resulted in the isolation of three new resorcylic acid lactones, neocosmosin A (2), neocosmosin B (3), and neocosmosin C (4). Three known resorcylic acid lactones, monocillin IV (1), monocillin II (5), and radicicol (6), were also isolated and identified. The structures of these compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analysis, mass spectrometric (ESIMS) data, and X-ray crystallography. Compounds 4-6 show good binding affinity for the human opioid receptors. These findings have important implications for evaluating the potential psychoactive effects with this class of compounds.

Secondary metabolites from Eupenicillium parvum and their in vitro binding affinity for human opioid and cannabinoid receptors.

Phytochemical investigation of the soil microfungus Eupenicillum parvum led to the isolation of two new compounds: a chromone derivative euparvione (1) and a new mycophenolic derivative euparvilactone (2), as well as thirteen known compounds. The structures of the new compounds were elucidated by means of extensive IR, NMR, and MS data and by comparison of data reported in the literature. The structure of the known compound 6 was confirmed by X-ray crystallography. Several isolated compounds were evaluated for in vitro binding assays using opioid receptors (subtypes δ, κ, and µ) and cannabinoid receptors (CB1 and CB2). Compound 10 displayed the best selective µ-opioid receptor and CB1 receptor binding affinities showing values of 47% and 52% at a 10 µM concentration, respectively. These findings provide insight into the potential therapeutic utility of this class of compounds.