Quinomycins with an unusual N-methyl-3-methylsulfinyl-alanine residue from a Streptomyces sp.

Four new echinomycin congeners, quinomycins M-P (1-4) were isolated from the cultures of the soil-derived Streptomyces sp. CPCC205575. The planar structures were determined by comprehensive analyses of NMR and HRESIMS/MS data. The absolute configurations were elucidated by the advanced Marfey's method combined with biosynthetic gene analysis. Compounds 1-4 represent the first examples of quinomycin-type natural products with the sulfur atom at the N,S-dimethylcysteine residue oxidized as a sulfoxide group forming the unusual N-methyl-3-methylsulfinyl-alanine residue. Bioassay results revealed that the oxidation of the sulfur atom at the Cys or Cys' residues led to dramatic decrease of cytotoxicity and antimicrobial activity.

Acremosides A-G, Sugar Alcohol-Conjugated Acyclic Sesquiterpenes from a Sponge-Derived Acremonium Species.

Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 µM) with no cytotoxicity (CC50 of >200 µM).

Antimicrobial and Anti-inflammatory Cyclic Tetrapeptides from the Co-cultures of Two Marine-Derived Fungi.

Violaceotides B-E (1-4), four new cyclic tetrapeptides, along with seven known compounds, were identified from the sponge-associated Aspergillus insulicola IMB18-072 co-cultivated with the marine-derived Alternaria angustiovoidea IMB20-805. Their structures were elucidated by extensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR, and MS/MS data. The absolute configurations were determined by the advanced Marfey's method. Compounds 2, 3, and violaceotide A (5) displayed selective antimicrobial activities against the aquatic pathogenic bacteria Edwardsiella tarda and E. ictaluri. In addition, compounds 1-5 showed inhibitory activities against the LPS-induced expression of the inflammatory mediator IL-6 in RAW264.7 cells at a concentration of 10 µM.

Anti-Biofilm Activity of Cocultimycin A against Candida albicans.

Candida albicans (C. albicans), the most common fungal pathogen, has the ability to form a biofilm, leading to enhanced virulence and antibiotic resistance. Cocultimycin A, a novel antifungal antibiotic isolated from the co-culture of two marine fungi, exhibited a potent inhibitory effect on planktonic C. albicans cells. This study aimed to evaluate the anti-biofilm activity of cocultimycin A against C. albicans and explore its underlying mechanism. Crystal violet staining showed that cocultimycin A remarkably inhibited biofilm formation in a dose-dependent manner and disrupted mature biofilms at higher concentrations. However, the metabolic activity of mature biofilms treated with lower concentrations of cocultimycin A significantly decreased when using the XTT reduction method. Cocultimycin A could inhibit yeast-to-hypha transition and mycelium formation of C. albicans colonies, which was observed through the use of a light microscope. Scanning electron microscopy revealed that biofilms treated with cocultimycin A were disrupted, yeast cells increased, and hypha cells decreased and significantly shortened. The adhesive ability of C. albicans cells treated with cocultimycin A to the medium and HOEC cells significantly decreased. Through the use of a qRT-PCR assay, the expression of multiple genes related to adhesion, hyphal formation and cell membrane changes in relation to biofilm cells treated with cocultimycin A. All these results suggested that cocultimycin A may be considered a potential novel molecule for treating and preventing biofilm-related C. albicans infections.

Prenylemestrins A and B: Two Unexpected Epipolythiodioxopiperazines with a Thioethanothio Bridge from Emericella sp. Isolated by Genomic Analysis.

Prenylemestrins A and B (1 and 2, respectively), two unusual epipolythiodioxopiperazines featuring a thioethanothio bridge instead of a polysulfide bridge, were isolated from the fungus Emericella sp. CPCC 400858 guided by genomic analysis. Their structures were determined by extensive spectroscopic data, NMR and ECD calculations, and X-ray diffraction analysis. A plausible biosynthetic pathway for 1 and 2 was proposed on the basis of gene cluster analysis. Prenylemestrins A and B exhibited cytotoxicities against human chronic myelocytic leukemia cell lines K562 and MEG-01.

Zelkovamycins F and G, Cyclopeptides with Cα-Methyl-threonine Residues, from an Endophytic Kitasatospora sp.

Zelkovamycins F and G (1 and 2), two new natural cyclic octapeptides possessing the unprecedented nonproteinogenic amino acid residues l-α-methyl-threonine and l-α-methyl-allo-threonine, respectively, along with four new analogues, zelkovamycins H-K (3-6), were identified from the endophytic Kitasatospora sp. CPCC 204717. Their structures were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data. The configurations of amino acid residues were determined by Marfey's analysis combined with NMR calculations. Compounds 1, 2, and 4 showed potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. The structure-activity relationship study revealed that the 2-methyl-3-oxobutyrine and sarcosine residues played important roles in their antibacterial activities. Zelkovamycin (7) and zelkovamycin E (8) exhibited significant antiviral activity against the hepatitis C virus.

Antimicrobial alkaloids from the root bark of Dictamnus dasycarpus.

Two new furoquinoline alkaloids, named 1'-oxo-isoplatydesmine (1) and demethoxyacrophylline (2), as well as 11 known alkaloids (3-13) were isolated from the root bark of Dictamnus dasycarpus Turcz. The structures of 1 and 2 were established by detailed spectroscopic elucidation, such as 1 D & 2 D NMR and HRMS, etc. The unexpected autoracemization of 1 was discussed based on the stereochemistry of reported dihydrofuroquinolines. Compounds 3-5 exhibited moderate inhibitory activities against Bacillus subtilis, Candida albicans, and Pseudomonas aeruginosa with MICs 32-64 µg/ml, revealing the active principles of D. dasycarpus for treating skin diseases in its traditional usage.

Acremopeptaibols A-F, 16-Residue Peptaibols from the Sponge-Derived Acremonium sp. IMB18-086 Cultivated with Heat-Killed Pseudomonas aeruginosa.

Six new 16-residue peptaibols, acremopeptaibols A-F (1-6), along with five known compounds, were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 grown in the presence of the autoclaved bacterium Pseudomonas aeruginosa on solid rice medium. The peptaibol sequences were established based on comprehensive analysis of 1D and 2D NMR spectroscopic data in conjunction with HRESIMS/MS experiments. The configurations of the amino acid residues were determined by advanced Marfey's analysis. Compounds 1-6 feature the lack of the highly conserved Thr6 and Hyp10 residues in comparison with other members of the SF3 subfamily peptaibols. A plausible biosynthetic pathway of compounds 1-6 was proposed on the basis of genomic analysis. Compounds 1, 5, 7, and 10 exhibited significant antimicrobial activity against Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus subtilis, and Candida albicans. Compounds 7-10 showed potent cytotoxicities against the A549 and/or HepG2 cancer cell lines.

Illihenin A: An Antiviral Sesquiterpenoid with a Cage-like Tricyclo[6.2.2.01,5]dodecane Skeleton from Illicium henryi.

Illihenin A (1), a novel sesquiterpenoid, was isolated from the roots of Illicium henryi. The structure was determined by spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction. Compound 1 represents a class of novel 5/7/6 tricyclic sesquiterpenoids featuring a rare cage-like tricyclo[6.2.2.01,5]dodecane core. A plausible biosynthetic pathway of 1 by rearrangement of allo-cedrane is proposed. Additionally, 1 showed potent antiviral activity against coxsackievirus B3 with an IC50 value of 2.87 µM.

Chemical characterization of the polar antibacterial fraction of the ethanol extract from Rosmarinus officinalis.

Rosmarinus officinalis L. has been widely used as a spice to extend the shelf life of foods. Most studies in the literature indicate that its essential oil is its major antibacterial component. In this study, a polar fraction from rosemary exhibited considerably stronger antibacterial activity against Bacillus subtilis than its essential oil. Guided by rapid characterization of the chemical compositions based on UPLC-Orbitrap-MS/MS, further investigation resulted in the isolation and identification of sixteen compounds. Among them, two new and six known compounds were identified in rosemary for the first time. Most isolated compounds exhibited significant antibacterial activities with minimum inhibitory concentration values of 2-128 µg/mL; however, these activities were weaker than that of the polar fraction. Thus, the polar fraction demonstrated a promising potential to serve as a food additive, as an alternative to the essential oil, because of its stronger antibacterial activity.

Zelkovamycins B-E, Cyclic Octapeptides Containing Rare Amino Acid Residues from an Endophytic Kitasatospora sp.

Four unusual cyclopeptides, zelkovamycins B-E (1-4), were isolated from an endophytic Kitasatospora sp. Zelkovamycin B was featured by an unprecedented 3-methyl-5-hydroxypyrrolidine-2,4-dione ring system linked to the cyclopeptide skeleton. Their structures and full configurations were established by spectroscopic analysis, Marfey's method, and NMR calculations. A plausible biosynthetic pathway for zelkovamycins was proposed based on gene cluster analysis. Zelkovamycin E displayed potent inhibitory activity against H1N1 influenza A virus.

Structural Revision and Absolute Configuration of Burnettramic Acid A.

The recently discovered antibiotic burnettramic acid A (1) and three new congeners, burnettramic acids C-E (2-4), were identified from the co-cultures of two marine Aspergillus strains. The structure of burnettramic acid A was revised on the basis of reinterpretation of the nuclear magnetic resonance (NMR) data and chemical derivatization. The full absolute configurations of burnettramic acids were established using the Mosher ester method and Marfey's analysis, combined with density functional theory calculation of NMR and electric circular dichroism data.

A natural solution to photoprotection and isolation of the potent polyene antibiotic, marinomycin A.

The photoprotection and isolation of marinomycin A using sporopollenin exine capsules (SpECs) derived from the spores of the plant Lycopodium clavatum is described. The marinomycins have a particularly short half-life in natural light, which severely impacts their potential biological utility given that they display potent antibiotic and anticancer activity. The SpEC encapsulation of the marinomycin A dramatically increases the half-life of the polyene macrodiolide to the direct exposure to UV radiation by several orders of magnitude, thereby making this a potentially useful strategy for other light sensitive bioactive agents. In addition, we report that the SpECs can also be used to selectively extract culture broths that contain the marinomycins, which provides a significantly higher recovery than with conventional XAD resins and provides concomitant photoprotection.

Broad-Spectrum Antiviral Natural Products from the Marine-Derived Penicillium sp. IMB17-046.

A new pyrazine derivative, trypilepyrazinol (1), a new α-pyrone polyketide, (+)-neocitreoviridin (2), and a new ergostane analogue, 3ß-hydroxyergosta-8,14,24(28)-trien-7-one (3), were isolated and characterized along with five known compounds from the marine-derived fungus Penicillium sp. IMB17-046. The structures of these new compounds were determined using spectroscopic data analyses (HRESIMS, 1D- and 2D-NMR), X-ray crystallography analysis, and TDDFT ECD calculation. Compounds 1 and 3 exhibited broad-spectrum antiviral activities against different types of viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza A virus (IAV), with IC50 values ranging from 0.5 to 7.7 µM. Compounds 1 and 2 showed antibacterial activities against Helicobacter pylori, a causative pathogen of various gastric diseases, with minimum inhibitory concentration (MIC) values of 1-16 µg/mL.

Raistrickindole A, an Anti-HCV Oxazinoindole Alkaloid from Penicillium raistrickii IMB17-034.

Raistrickindole A (1), a new indole diketopiperazine alkaloid containing an unusual pyrazino[1',2':2,3][1,2]oxazino[6,5- b]indole tetraheterocyclic ring system, a new benzodiazepine derivative, raistrickin (2), and the known haenamindole (3) and sclerotigenin (4) were isolated from the marine-derived fungus Penicillium raistrickii IMB17-034. Their structures were elucidated by extensive spectroscopic analyses and TDDFT calculations of the NMR and ECD data. Compounds 1 and 2 showed inhibitory activities against the hepatitis C virus.

Isocoumarindole A, a Chlorinated Isocoumarin and Indole Alkaloid Hybrid Metabolite from an Endolichenic Fungus Aspergillus sp.

Isocoumarindole A (1), a novel polyketide synthetase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolite, was isolated from the endolichenic fungus Aspergillus sp. CPCC 400810. The structure of isocoumarindole A (1) was featured by an unprecedented skeleton containing chlorinated isocoumarin and indole diketopiperazine alkaloid moieties linked by a carbon-carbon bond, which was determined by a combination of spectroscopic analyses, Marfey's method, and calculations of NMR chemical shifts, ECD spectra, and optical rotation values. Isocoumarindole A showed significant cytotoxicity and mild antifungal activities.

Tetracenomycin X Exerts Antitumour Activity in Lung Cancer Cells through the Downregulation of Cyclin D1.

Tetracenomycin X (Tcm X) has been reported to have antitumour activity in various cancers, but there have not been any studies on its activity with respect to lung cancer to date. Therefore, this study aims to investigate the anti-lung cancer activity of Tcm X. In this study, we found that tetracenomycin X showed antitumour activity in vivo and selectively inhibited the proliferation of lung cancer cells without influencing lung fibroblasts. In addition, apoptosis and autophagy did not contribute to the antitumour activity. Tetracenomycin X exerts antitumour activity through cell cycle arrest induced by the downregulation of cyclin D1. To explore the specific mechanism, we found that tetracenomycin X directly induced cyclin D1 proteasomal degradation and indirectly downregulated cyclin D1 via the activation of p38 and c-JUN proteins. All these findings were explored for the first time, which indicated that tetracenomycin X may be a powerful antimitotic class of anticancer drug candidates for the treatment of lung cancer in the future.

Seco-Tetracenomycins from the Marine-Derived Actinomycete Saccharothrix sp. 10-10.

Six new tetracenomycin congeners, saccharothrixones E⁻I (1⁻5) and 13-de-O-methyltetracenomycin X (6), were isolated from the rare marine-derived actinomycete Saccharothrix sp. 10-10. Their structures were elucidated by spectroscopic analysis and time-dependent density functional theory (TDDFT)-electronic circular dichroism (ECD) calculations. Saccharothrixones G (3) and H (4) are the first examples of tetracenomycins featuring a novel ring-A-cleaved chromophore. Saccharothrixone I (5) was determined to be a seco-tetracenomycin derivative with ring-B cleavage. The new structural characteristics, highlighted by different oxidations at C-5 and cleavages in rings A and B, enrich the structural diversity of tetracenomycins and provide evidence for tetracenomycin biosynthesis. Analysis of the structure⁻activity relationship of these compounds confirmed the importance of the planarity of the naphthacenequinone chromophore and the methylation of the polar carboxy groups for tetracenomycin cytotoxicity.

Identification and Proposed Relative and Absolute Configurations of Niphimycins C-E from the Marine-Derived Streptomyces sp. IMB7-145 by Genomic Analysis.

Analysis of the whole genome sequence of Streptomyces sp. IMB7-145 revealed the presence of seven type I polyketide synthase biosynthetic gene clusters, one of which was highly homologous to the biosynthetic gene cluster of azalomycin F. Detailed bioinformatic analysis of the modular organization of the PKS gene suggested that this gene is responsible for niphimycin biosynthesis. Guided by genomic analysis, a large-scale cultivation ultimately led to the discovery and characterization of four new niphimycin congeners, namely, niphimycins C-E (1-3) and 17-O-methylniphimycin (4). The configurations of most stereocenters of niphimycins have not been determined to date. In the present study, the relative configurations were elucidated by spectroscopic analysis, including J-based analysis and the CNMR database method. Further, the full absolute configurations of niphimycins were completely proposed for the first time based on biosynthetic gene cluster analysis of the ketoreductase and enoylreductase domains for hydroxy- and methyl-bearing stereocenters. Compounds 1, 3, 4, and niphimycin Iα (5) showed antimicrobial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci (MIC: 8-64 µg/mL), as well as cytotoxicity against the human HeLa cancer cell line (IC50: 3.0-9.0 µM). In addition, compounds 1 and 5 displayed significant activity against several Mycobacterium tuberculosis clinical isolates (MIC: 4-32 µg/mL).

Neo-actinomycins A and B, natural actinomycins bearing the 5H-oxazolo[4,5-b]phenoxazine chromophore, from the marine-derived Streptomyces sp. IMB094.

Neo-actinomycins A and B (1 and 2), two new natural actinomycins featuring an unprecedented tetracyclic 5H-oxazolo[4,5-b]phenoxazine chromophore, were isolated from the marine-derived actinomycete Streptomyces sp. IMB094. Their structures were elucidated by spectroscopic analyses. The presence of this ring system was proposed to originate from a condensation between actinomycin D (3) with α-ketoglutarate and pyruvate, respectively. Compound 1 showed potent cytotoxic activities against human cancer HCT116 and A549 cell lines in the nanomolar range (IC50: 38.7 and 65.8 nM, respectively) and moderate antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) strains.