Chemical Space Covered by Applicability Domains of Quantitative Structure-Property Relationships and Semiempirical Relationships in Chemical Assessments.

A significant number of chemicals registered in national and regional chemical inventories require assessments of their potential "hazard" concerns posed to humans and ecological receptors. This warrants knowledge of their partitioning and reactivity properties, which are often predicted by quantitative structure-property relationships (QSPRs) and other semiempirical relationships. It is imperative to evaluate the applicability domain (AD) of these tools to ensure their suitability for assessment purpose. Here, we investigate the extent to which the ADs of commonly used QSPRs and semiempirical relationships cover seven partitioning and reactivity properties of a chemical "space" comprising 81,000+ organic chemicals registered in regulatory and academic chemical inventories. Our findings show that around or more than half of the chemicals studied are covered by at least one of the commonly used QSPRs. The investigated QSPRs demonstrate adequate AD coverage for organochlorides and organobromines but limited AD coverage for chemicals containing fluorine and phosphorus. These QSPRs exhibit limited AD coverage for atmospheric reactivity, biodegradation, and octanol-air partitioning, particularly for ionizable organic chemicals compared to nonionizable ones, challenging assessments of environmental persistence, bioaccumulation capability, and long-range transport potential. We also find that a predictive tool's AD coverage of chemicals depends on how the AD is defined, for example, by the distance of a predicted chemical from the centroid of the training chemicals or by the presence or absence of structural features.

Origin of the 6/5/6/5 Tetracyclic Cyclopiazonic Acids.

The natural product α-cyclopiazonic acid (α-CPA) is a very potent Ca2+-ATPase inhibitor. The CPA family of compounds comprise over 80 chemical entities with at least five distinct skeletons. While α-CPA features a canonical 6/5/6/5/5 skeleton, the 6/5/6/5 skeleton is the most prevalent among the CPA family. However, the origin of the unique tetracyclic skeleton remains unknown. The 6/5/6/5-type CPAs may derive from a precursor of acetoacetyl-l-tryptophan (AATrp) generated from a hypothetic thioesterase-like pathway. Alternatively, cleavage of the tetramic acid ring would also result in the formation of the 6/5/6/5 scaffold. Aspergillus oryzae HMP-F28 is a marine sponge-associated filamentous fungus known to produce CPAs that act as primary neurotoxins. To elucidate the origin of this subfamily of CPAs, we performed homologous recombination and genetic engineering experiments on strain HMP-F28. Our results are supportive of the ring cleavage pathway through which the tetracyclic 6/5/6/5-type CPAs are generated from 6/5/6/5/5-type pentacyclic CPAs.

Characterization and Biosynthetic Regulation of Isoflavone Genistein in Deep-Sea Actinomycetes Microbacterium sp. B1075.

Deep-sea environments, as relatively unexplored extremes within the Earth's biosphere, exhibit notable distinctions from terrestrial habitats. To thrive in these extreme conditions, deep-sea actinomycetes have evolved unique biochemical metabolisms and physiological capabilities to ensure their survival in this niche. In this study, five actinomycetes strains were isolated and identified from the Mariana Trench via the culture-dependent method and 16S rRNA sequencing approach. The antimicrobial activity of Microbacterium sp. B1075 was found to be the most potent, and therefore, it was selected as the target strain. Molecular networking analysis via the Global Natural Products Social Molecular Networking (GNPS) platform identified 25 flavonoid compounds as flavonoid secondary metabolites. Among these, genistein was purified and identified as a bioactive compound with significant antibacterial activity. The complete synthesis pathway for genistein was proposed within strain B1075 based on whole-genome sequencing data, with the key gene being CHS (encoding chalcone synthase). The expression of the gene CHS was significantly regulated by high hydrostatic pressure, with a consequent impact on the production of flavonoid compounds in strain B1075, revealing the relationship between actinomycetes' synthesis of flavonoid-like secondary metabolites and their adaptation to high-pressure environments at the molecular level. These results not only expand our understanding of deep-sea microorganisms but also hold promise for providing valuable insights into the development of novel pharmaceuticals in the field of biopharmaceuticals.

A Hadal Streptomyces-Derived Echinocandin Acylase Discovered through the Prioritization of Protein Families.

Naturally occurring echinocandin B and FR901379 are potent antifungal lipopeptides featuring a cyclic hexapeptide nucleus and a fatty acid side chain. They are the parent compounds of echinocandin drugs for the treatment of severe fungal infections caused by the Candida and Aspergilla species. To minimize hemolytic toxicity, the native fatty acid side chains in these drug molecules are replaced with designer acyl side chains. The deacylation of the N-acyl side chain is, therefore, a crucial step for the development and manufacturing of echinocandin-type antibiotics. Echinocandin E (ECE) is a novel echinocandin congener with enhanced stability generated via the engineering of the biosynthetic machinery of echinocandin B (ECB). In the present study, we report the discovery of the first echinocandin E acylase (ECEA) using the enzyme similarity tool (EST) for enzymatic function mining across protein families. ECEA is derived from Streptomyces sp. SY1965 isolated from a sediment collected from the Mariana Trench. It was cloned and heterologously expressed in S. lividans TK24. The resultant TKecea66 strain showed efficient cleavage activity of the acyl side chain of ECE, showing promising applications in the development of novel echinocandin-type therapeutics. Our results also provide a showcase for harnessing the essentially untapped biodiversity from the hadal ecosystems for the discovery of functional molecules.

Isolation and Structure Elucidation of New Metabolites from the Mariana-Trench-Associated Fungus Aspergillus sp. SY2601.

Fungi are important resource for the discovery of novel bioactive natural products. This study investigated the metabolites produced by Mariana-Trench-associated fungus Aspergillus sp. SY2601 in EY liquid and rice solid media, resulting in the isolation and structure determination of 28 metabolites, including five new compounds, asperindopiperazines A-C (1-3), 5-methoxy-8,9-dihydroxy-8,9-deoxyaspyrone (21), and 12S-aspertetranone D (26). Structures of the new compounds were elucidated based on extensive NMR spectral analyses, HRESIMS data, optical rotation, ECD, and 13C NMR calculations. The new compound 12S-aspertetranone D (26) exhibited antibacterial activity against both methicillin-resistant Staphylococcus aureus and Escherichia coli with MIC values of 3.75 and 5 µg/mL, respectively.

Antiglioma Natural Products from the Marine-Associated Fungus Penicillium sp. ZZ1750.

Marine-derived Penicillium fungi are one of the most important sources for the discovery of new bioactive natural products. This study characterized the isolation, structures, and antiglioma activities of twelve compounds, including three novel ones-penipyridinone B (1), 11S-(-)-penilloid A (2), and 11R,14E-(+)-penilloid A (3)-from the marine fungus Penicillium sp. ZZ1750. The structures of the novel compounds were determined via extensive nuclear magnetic resonance (NMR) spectroscopic analyses, high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, Mosher's method, optical rotation (OR) calculations, and electronic circular dichroism (ECD) calculations. Penipyridinone B represents the first example of its structural type and showed potent antiglioma activity, with IC50 values of 2.45 µM for U87MG cells and 11.40 µM for U251 cells. The known compounds of questiomycin A (9) and xanthocillin X (10) also showed antiproliferative activity against both U87MG and U251 cells, with IC50 values of 13.65 µM to 22.56 µM. The antiglioma activity of questiomycin A and xanthocillin X may be related to the promotion of reactive oxygen species (ROS) production, the reduction of mitochondrial membrane potential (MMP), and the enhancement of caspase-3 enzyme activity.

LuxS quorum sensing system mediating Lactobacillus plantarum probiotic characteristics.

Lactobacillus plantarum is one of common probiotics in fermented foods. Quorum sensing (QS) is a common communication way within bacteria. It is not clear whether the probiotic properties of L. plantarum mediated by QS. Here, Lb. plantarum YM-4-3 was examined for resistance of pH, bile, antimicrobial and luxS gene expression pattern. The study found that: (1) the supernatant of YM-4-3 had bacteriostatic effect to Escherichia coli O157:H7, Listeria monocytogenes and Staphylococcus aureus; (2) Lb. plantarum YM-4-3 shown tolerance property to the strongest acid culture that pH value of 3; (3) the bile tolerance of Lb. plantarum YM-4-3 was significant difference with the growth stage, the early exponential phase of the growth culture can tolerate bile of 0.4% (w/v), while the stationary growth stage can only tolerate bile of 0.2%; (4) Lb. plantarum YM-4-3 luxS gene was contrary expression along with the growth. (5) Compared with the wild-type strain, the adhesion ability of Lb. plantarum YM-4-3 ΔluxS was decreased obviously. These results showed that AI-2 LuxS quorum sensing system mediating Lb. plantarum acid, bile tolerance, antimicrobial and adhesion of probiotics.

Evaluation of the antiproliferative activity of 106 marine microbial metabolites against human lung cancer cells and potential antiproliferative mechanism of purpuride G.

A total of 106 marine microbial metabolites were evaluated for their antiproliferative activity against human lung cancer cells. Results showed that 23 compounds exhibited activity in inhibiting the proliferation of A549 and H157 cells with IC50 values ranging from 1.5 to 48.2 µM. Pyrrospirone F, chrysophanol, physcion, and purpuride G are the four most active compounds with IC50 values of 1.5-7.3 µM. Further investigation of purpuride G (a newly discovered sesquiterpene lactone) demonstrated its potent antiproliferative activity against six different lung cancer cells of A549, H157, H460, H1299, H1703, and PC9 with IC50 values of 2.1-3.3 µM. The antiproliferative activity of purpuride G against cancer cells is related to block cell cycle, induce apoptosis through regulating the apoptotic proteins Bcl-2 and Bax, and inhibit glycolysis by downregulating two key glycolytic enzymes of hexokinase 2 and pyruvate kinase M2.

New Antiproliferative Compounds against Glioma Cells from the Marine-Sourced Fungus Penicillium sp. ZZ1750.

Seven novel compounds, namely peniresorcinosides A-E (1-5), penidifarnesylin A (6), and penipyridinone A (7), together with the 11 known ones 8-17, were isolated from a culture of the marine-associated fungus Penicillium sp. ZZ1750 in rice medium. The structures of the new compounds were established based on their high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, extensive nuclear magnetic resonance (NMR) spectroscopic analyses, chemical degradation, Mosher's method, 13C-NMR calculations, electronic circular dichroism (ECD) calculations, and single crystal X-ray diffraction. Peniresorcinosides A (1) and B (2) are rare glycosylated alkylresorcinols and exhibited potent antiglioma activity, with IC50 values of 4.0 and 5.6 µM for U87MG cells and 14.1 and 9.8 µM for U251 cells, respectively.

Antiproliferative Activity and Potential Mechanism of Marine-Sourced Streptoglutarimide H against Lung Cancer Cells.

In 2019, streptoglutarimide H (SGH) was characterized as a new glutarimide from the secondary metabolites produced by a marine-derived actinomycete Streptomyces sp. ZZ741 and shown to have in vitro antiglioma activity. However, the antiproliferative activity and potential mechanism of SGH against lung cancer cells have not yet been characterized. This study demonstrated that SGH significantly inhibited the proliferation of different lung cancer cells. In terms of mechanism of action, SGH downregulated cell cycle- and nucleotide synthesis-related proteins to block cell cycle at G0/G1 phase, reduced the expression levels of glycolytic metabolic enzymes to inhibit glycolysis, and downregulated the important cancer transcription factor c-Myc and the therapeutic target deubiquitinase USP28. Potent anticancer activity and multiple mechanisms indicated SGH to be a novel antitumor compound against lung cancer cells.

Bioactive Alkaloids from the Actinomycete Actinoalloteichus sp. ZZ1866.

The new alkaloids marinacarbolines E-Q (1-10, 12-14), caerulomycin N (15), and actinoallonaphthyridine A (16), together with the known marinacarboline C (11) and cyanogramide (17), were isolated from the actinomycete Actinoalloteichus sp. ZZ1866. The structures of the isolated compounds were elucidated based on their HRESIMS data, extensive NMR spectroscopic analyses, Mosher's method, ECD calculations, single-crystal X-ray diffraction analysis, and chemical degradation studies. Marinacarbolines E-L (1-8) share an indole-pyridone-imidazole tetracyclic skeleton, which is the first example of this kind of skeleton. Caerulomycin N (15) and cyanogramide (17) exhibited cytotoxic activity against both human glioma U251 and U87MG cells with IC50 values of 2.0-7.2 µM. Marinacarbolines E (1), G (3), I (5), and M (9) showed cytotoxic activity against U87MG cells with IC50 values of 2.3-8.9 µM.

New Antifungal Metabolites from the Mariana Trench Sediment-Associated Actinomycete Streptomyces sp. SY1965.

New streptothiazolidine A (1), streptodiketopiperazines A (2) and B (3), and (S)-1-(3-ethylphenyl)-1,2-ethanediol (4), together with eight known compounds (5-12), were isolated from the Mariana Trench sediment-associated actinomycete Streptomyces sp. SY1965. The racemic mixtures of (±)-streptodiketopiperazine (2 and 3) and (±)-1-(3-ethylphenyl)-1,2-ethanediol (4 and 5) were separated on a chiral high-performance liquid chromatography (HPLC) column. Structures of the new compounds were elucidated by their high-resolution electrospray ionization mass spectroscopy (HRESIMS) data and extensive nuclear magnetic resonance (NMR) spectroscopic analyses. Streptothiazolidine A is a novel salicylamide analogue with a unique thiazolidine-contained side chain and its absolute configuration was established by a combination of nuclear Overhauser effect spectroscopy (NOESY) experiment, electronic circular dichroism (ECD) and 13C NMR calculations. New streptothiazolidine A (1) and streptodiketopiperazines A (2) and B (3) showed antifungal activity against Candida albicans with MIC values of 47, 42, and 42 g/mL, respectively.

Bioactive Metabolites from the Mariana Trench Sediment-Derived Fungus Penicillium sp. SY2107.

Mariana Trench sediments are enriched in microorganisms, however, the structures and bioactivities of their secondary metabolites are not very known. In this study, a fungus Penicillium sp. SY2107 was isolated from a sample of Mariana Trench sediment collected at a depth of 11000 m and an extract prepared from the culture of this fungus in rice medium showed antimicrobial activities. Chemical investigation on this active extract led to the isolation of 16 compounds, including one novel meroterpenoid, named andrastone C. Structure of the new compound was elucidated based on high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, extensive nuclear magnetic resonance (NMR) spectroscopic analyses and a single crystal X-ray diffraction. The crystal structure of a known meroterpenoid andrastone B was also reported in this study. Both andrastones B and C exhibited antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Candida albicans with minimum inhibitory concentration (MIC) values in a range from 6 to 13 g/mL.

Coupled Cation-Anion Dynamics Enhances Cation Mobility in Room-Temperature Superionic Solid-State Electrolytes.

Single-ion conducting solid electrolytes are gaining tremendous attention as essential materials for solid-state batteries, but a comprehensive understanding of the factors that dictate high ion mobility remains elusive. Here, for the first time, we use a combination of the Maximum Entropy Method analysis of room-temperature neutron powder diffraction data, ab initio molecular dynamics, and joint-time correlation analysis to demonstrate that the dynamic response of the anion framework plays a significant role in the new class of fast ion conductors, Na11Sn2PnX12 (Pn = P, Sb; X = S, Se). Facile [PX4]3- anion rotation exists in superionic Na11Sn2PS12 and Na11Sn2PSe12, but greatly hindered [SbS4]3- rotational dynamics are observed in their less conductive analogue, Na11Sn2SbS12. Along with introducing dynamic frustration in the energy landscape, the fluctuation caused by [PX4]3- anion rotation is firmly proved to couple to and facilitate long-range cation mobility, by transiently widening the bottlenecks for Na+-ion diffusion. The combined analysis described here resolves the role of the long-debated paddle-wheel mechanism, and is the first direct evidence that anion rotation significantly enhances cation migration in rotor phases. The joint-time correlation analysis developed in our work can be broadly applied to analyze coupled cation-anion interplay where traditional transition state theory does not apply. These findings deliver important insights into the fundamentals of ion transport in solid electrolytes. Invoking anion rotational dynamics provides a vital strategy to enhance cation conductivity and serves as an additional and universal design principle for fast ion conductors.

Bioactive Streptoglutarimides A-J from the Marine-Derived Streptomyces sp. ZZ741.

The new streptoglutarimides A-J (1-10) and the known streptovitacin A (11) were isolated from a marine-derived actinomycete, Streptomyces sp. ZZ741. Structures of the isolated compounds were elucidated based on their HRESIMS data, extensive NMR spectroscopic analyses, ECD calculations, Mosher's method, and a single-crystal X-ray diffraction experiment. Streptoglutarimide H (8) and streptovitacin A (11) showed potent antiproliferative activity against human glioma U87MG and U251 cells with IC50 values of 1.5-3.8 µM for 8 and 0.05-0.22 µM for 11. All isolated compounds exhibited antimicrobial activity with MIC values of 9-11 µg/mL against methicillin-resistant Staphylococcus aureus, 8-12 µg/mL against Escherichia coli, and 8-20 µg/mL against Candida albicans.

Novel Bioactive Penicipyrroether A and Pyrrospirone J from the Marine-Derived Penicillium sp. ZZ380.

The marine-sourced fungus Penicillium sp. ZZ380 was previously reported to have the ability to produce a series of new pyrrospirone alkaloids. Further investigation on this strain resulted in the isolation and identification of novel penicipyrroether A and pyrrospirone J. Each of them represents the first example of its structural type, with a unique 6/5/6/5 polycyclic fusion that is different from the 6/5/6/6 fused ring system for the reported pyrrospirones. Their structures were elucidated by extensive nuclear magnetic resonance (NMR) and high resolution electrospray ionization mass spectroscopy (HRESIMS) spectroscopic analyses, electronic circular dichroism (ECD) and 13C NMR calculations and X-ray single crystal diffraction. Penicipyrroether A showed potent antiproliferative activity against human glioma U87MG and U251 cells with half maximal inhibitory concentration (IC50) values of 1.64-5.50 µM and antibacterial inhibitory activity with minimum inhibitory concentration (MIC) values of 1.7 µg/mL against methicillin-resistant Staphylococcus aureus and 3.0 µg/mL against Escherichia coli.

Novel Antimicrobial Indolepyrazines A and B from the Marine-Associated Acinetobacter sp. ZZ1275.

Two new alkaloids indolepyrazines A (1) and B (2) were isolated from the marine-derived Acinetobacter sp. ZZ1275. Their structures were elucidated through extensive nuclear magnetic resonance (NMR) spectroscopic analyses, high resolution electrospray ionization mass spectroscopy (HRESIMS) data, and electronic circular dichroism (ECD) calculation. Indolepyrazine A represents the first example of alkaloids with an indole-pyrazine-oxindole skeleton. Both 1 and 2 showed antimicrobial activities against methicillin-resistant Staphylococcus aureus, Escherichia coli, and Candida albicans with minimum inhibitory concentration (MIC) values of 12 µg/mL, 8⁻10 µg/mL, and 12⁻14 µg/mL, respectively.

Adenylyl cyclase 1 as a major isoform to generate cAMP signaling for apoA-1-mediated cholesterol efflux pathway.

HDL apoA-1-mediated cholesterol efflux pathway requires multiple cellular proteins and signal transduction processes, including adenylyl cyclase (AC)/cAMP signaling. Due to the existence of multiple transmembrane AC isoforms, it was not known how many AC isoforms are expressed and which ones are essential for cholesterol efflux in macrophage foam cells. These questions were investigated in THP-1 macrophages in this study. Quantitative RT-PCR detected mRNAs for all nine transmembrane AC isoforms, but only the mRNA and protein of the AC1 isoform were consistently upregulated by cholesterol loading and apoA-1. AC1 shRNA interference decreased AC1 mRNA and protein levels, resulting in reduction of apoA-1-mediated cAMP production and cholesterol efflux, while the intracellular cholesterol levels remained high. Confocal microscopy showed that apoA-1 promoted translocation of cholesterol and formation of cholesterol-apoA-1 complexes (protrusions) on the cholesterol-loaded macrophage surface. AC1 shRNA-interfered macrophages showed no translocation of cholesterol to the cell surface. AC1 shRNA interference also disrupted cellular localization of the intracellular cholesterol indicator protein adipophillin, and the expression as well as surface translocation of ABCA1. Together, our results show that AC1 is a major isoform for apoA-1-activated cAMP signaling to promote cholesterol transport and exocytosis to the surface of THP-1 macrophage foam cells.

Bioactive Penicipyrrodiether A, an Adduct of GKK1032 Analogue and Phenol A Derivative, from a Marine-Sourced Fungus Penicillium sp. ZZ380.

Penicipyrrodiether A, an adduct of GKK1032 analogue and phenol A derivative, was isolated from a culture of marine-associated fungus Penicillium sp. ZZ380 and represents the first example of this type of fungal metabolite. Its structure was elucidated by extensive spectroscopic analyses, including 1D- and 2D-NMR, HRESIMS, MS/MS, and electronic circular dichroism calculation as well as single-crystal X-ray diffraction. Penicipyrrodiether A showed antibacterial activity in inhibiting the growth of methicillin-resistant Staphylococcus aureus with a MIC value of 5.0 µg/mL. Its plausible pathway for biosynthesis has been proposed.

Anti-glioma Efficacy and Mechanism of Action of Tripolinolate A from Tripolium pannonicum.

Tripolinolate A as a new bioactive phenolic ester was previously isolated from a halophyte of Tripolium pannonicum. However, the in vitro and in vivo anti-glioma effects and mechanism of tripolinolate A have not been investigated. This study has demonstrated that (1) tripolinolate A inhibited the proliferation of different glioma cells with IC50 values of 7.97 to 14.02 µM and had a significant inhibitory effect on the glioma growth in U87MG xenograft nude mice, (2) tripolinolate A induced apoptosis in glioma cells by downregulating the expressions of antiapoptotic proteins and arrested glioma cell cycle at the G2/M phase by reducing the expression levels of cell cycle regulators, and (3) tripolinolate A also remarkably reduced the expression levels of several glioma metabolic enzymes and transcription factors. All data together suggested that tripolinolate A had significant in vitro and in vivo anti-glioma effects and the regulation of multiple tumor-related regulators and transcription factors might be responsible for the activities of tripolinolate A against glioma.