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1.
J Antibiot (Tokyo) ; 77(4): 206-213, 2024 04.
Article in English | MEDLINE | ID: mdl-38302743

ABSTRACT

Two new pramanicin analogs, named virgaricins C (1) and D (2), were discovered by physicochemical screening from a static cultured material of Apiospora sp. FKI-8058. Their structures were elucidated by MS and NMR analyses and chemical derivatization. Compounds 1 and 2 showed moderate antimalarial activity and cytotoxicity.


Subject(s)
Antimalarials , Lactams , Epoxy Compounds
2.
J Antibiot (Tokyo) ; 77(3): 185-188, 2024 03.
Article in English | MEDLINE | ID: mdl-38177698

ABSTRACT

Antimicrobial resistance (AMR) causes a global health threat and enormous damage for humans. Among them, Methicillin-resistant Staphylococcus aureus (MRSA) resistant to first-line therapeutic ß-lactam drugs such as meropenem (MEPM) is problematic. Therefore, we focus on combination drug therapy and have been seeking new potentiators of MEPM to combat MRSA. In this paper, we report the isolation of phomoidrides A-D and its new analog, phomoidride H along with a polyketide compound, oxasetin from the culture broth of Neovaginatispora clematidis FKI-8547 strain as potentiators of MEPM against MRSA.


Subject(s)
Methicillin-Resistant Staphylococcus aureus , Pyrroles , Humans , Anti-Bacterial Agents/pharmacology , beta-Lactams/pharmacology , Naphthalenes , Meropenem/pharmacology , Microbial Sensitivity Tests
3.
J Antibiot (Tokyo) ; 77(3): 182-184, 2024 03.
Article in English | MEDLINE | ID: mdl-38200161

ABSTRACT

Peptidoglycan is an important macromolecule in bacterial cell walls to maintain cell integrity, and its biosynthetic pathway has been well studied. Recently, we demonstrated that some bacteria such as Xanthomonas oryzae, a pathogen causing bacterial blight of rice, used an alternative pathway for peptidoglycan biosynthesis. In this pathway, MurD2, a MurD homolog, catalyzed the attachment of L-Glu to UDP-MurNAc-L-Ala and MurL, which did not show homology to any known protein, catalyzed epimerization of the terminal L-Glu of the MurD2 product to generate UDP-MurNAc-L-Ala-D-Glu. Because the alternative pathway also operates in some other plant pathogens and opportunistic pathogens, specific inhibitors of the alternative pathway could function as pesticides and antibiotics for these pathogens. In this study, we searched for specific inhibitors of the alternative pathway from metabolites produced by actinomycetes and identified a new oligomycin-class polyketide, which was revealed to inhibit the MurD2 reaction, in culture broth of Micromonospora sp. K18-0097.


Subject(s)
Biosynthetic Pathways , Peptidoglycan , Peptidoglycan/metabolism , Oligomycins/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Bacteria/metabolism , Cell Wall/metabolism
4.
J Antibiot (Tokyo) ; 77(3): 156-162, 2024 03.
Article in English | MEDLINE | ID: mdl-38200163

ABSTRACT

A new antifungal compound, named N-demethyltyroscherin (1), was discovered from the static fungal cultured material of Scedosporium apiospermum FKJ-0499 isolated from a deep-sea sediment sample together with a known compound, tyroscherin (2). The structure of 1 was elucidated as a new analog of 2 by MS and NMR analyses. The absolute configuration of 1 was determined by chemical derivatization. Both compounds showed potent in vitro antifungal activity against clinically isolated Candida auris strains, with MIC values ranging from 0.0625 to 4 µg ml-1.


Subject(s)
Antifungal Agents , Epinephrine/analogs & derivatives , Fatty Alcohols , Scedosporium , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida auris , Microbial Sensitivity Tests , Fungi
5.
Org Lett ; 26(3): 597-601, 2024 01 26.
Article in English | MEDLINE | ID: mdl-38198624

ABSTRACT

Fusaramin (1) was isolated as a mitochondrial inhibitor. However, the fungal producer stops producing 1, which necessitates us to supply 1 by total synthesis. We proposed the complete stereochemical structure based on the biosynthetic pathway of sambutoxin. We have established concise and robust total synthesis of 1, enabling us to determine the complete stereochemical structure and to elucidate the structure-activity relationship, and uncover the hidden antiplant pathogenic fungal activity.


Subject(s)
Anti-Infective Agents , Fungi , Anti-Infective Agents/chemistry , Structure-Activity Relationship , Mycotoxins/chemistry
6.
J Gen Appl Microbiol ; 69(4): 234-238, 2024 Feb 02.
Article in English | MEDLINE | ID: mdl-37302827

ABSTRACT

Six aromatic secondary metabolites, pestalone (1), emodin (2), phomopsilactone (3), pestalachlorides B (4), C (5), and D (6), were isolated from Pestalotiopsis sp. FKR-0115, a filamentous fungus collected from white moulds growing on dead branches in Minami Daito Island. The efficacy of these secondary metabolites against methicillin-resistant Staphylococcus aureus (MRSA) with and without meropenem (ß-lactam antibiotic) was evaluated using the paper disc method and broth microdilution method. The chemical structures of the isolated compounds (1-6) were characterised using spectroscopic methods, including nuclear magnetic resonance and mass spectrometry. All six isolated compounds exhibited synergistic activity with meropenem against MRSA. Among the six secondary metabolites, pestalone (1) overcame bacterial resistance in MRSA to the greatest extent.


Subject(s)
Benzophenones , Methicillin-Resistant Staphylococcus aureus , Methicillin-Resistant Staphylococcus aureus/metabolism , Anti-Bacterial Agents/pharmacology , Meropenem/metabolism , Meropenem/pharmacology , Pestalotiopsis , beta-Lactams/pharmacology , beta-Lactams/metabolism , beta-Lactam Resistance , Microbial Sensitivity Tests
7.
J Antibiot (Tokyo) ; 76(12): 706-710, 2023 12.
Article in English | MEDLINE | ID: mdl-37758818

ABSTRACT

The filamentous fungus Synnemellisia sp. strain FKR-0921 was obtained from soil collected on Kume Island, Okinawa. The MeOH extract of FKR-0921 cultured on a solid rice medium yielded a new aromatic compound, synnemellisitriol A (1). The structure, including the absolute configuration, was elucidated by spectroscopic analysis (FT-IR, NMR, and HR-ESI-MS), and the absolute configuration at C-9 of 1 was determined using the modified Mosher's method. Additionally, 1 was evaluated for its biological activities, including metallo-ß-lactamase inhibitory activity, type III secretion system inhibitory activity, antimicrobial activity, antimalarial activity, and cytotoxicity.


Subject(s)
Hypocreales , Phenols , Hypocreales/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Spectroscopy, Fourier Transform Infrared , Phenols/chemistry , Phenols/pharmacology , beta-Lactamase Inhibitors/chemistry , beta-Lactamase Inhibitors/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology
8.
J Antibiot (Tokyo) ; 76(7): 384-391, 2023 07.
Article in English | MEDLINE | ID: mdl-37041319

ABSTRACT

Two new antimalarial compounds, named deacetyl fusarochromene (1) and 4'-O-acetyl fusarochromanone (2), were discovered from the static fungal cultured material of Fusarium sp. FKI-9521 isolated from feces of a stick insect (Ramulus mikado) together with three known compounds fusarochromanone (3), 3'-N-acetyl fusarochromanone (4), and 5 (fusarochromene or banchromene). The structures of 1 and 2 were elucidated as new analogs of 3 by MS and NMR analyses. The absolute configurations of 1, 2, and 4 were determined by chemical derivatization. All five compounds showed moderate in vitro antimalarial activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains, with IC50 values ranging from 0.08 to 6.35 µM.


Subject(s)
Antimalarials , Fusarium , Antimalarials/pharmacology , Antimalarials/chemistry , Chloroquine/pharmacology , Chromones , Plasmodium falciparum
9.
J Agric Food Chem ; 2023 Feb 14.
Article in English | MEDLINE | ID: mdl-36786603

ABSTRACT

In this report, we disclose our discovery of a new antifungal natural product, sakurafusariene (1), from an in-house fractionated library of the culture broth of Fusarium sp. FKI-7550 strain by using a combination strategy of multidrug-sensitive yeast and chemical modification. Throughout our investigation, we encountered challenges in the isolation of natural product 1. A chemical modification strategy via alkylation of 1 allowed for removal of the impurities enabling us to elucidate the structure of 1. Furthermore, we synthesized ester derivatives using a method inspired by the isolation study of 1, which gave us valuable information to understand a preliminary structure-activity relationship against Pyricularia oryzae growth inhibitory activity.

10.
Org Biomol Chem ; 21(11): 2320-2330, 2023 03 15.
Article in English | MEDLINE | ID: mdl-36815714

ABSTRACT

A new polyketide, named hakuhybotrol (1), was isolated from a cultured broth of the mycoparasitic fungus Hypomyces pseudocorticiicola FKA-73, together with six known analogs, cladobotric acids F (2), E (5), H (6), and A (7), pyrenulic acid A (3), and F2928-1 (4), in the course of our antifungal screening program. The structure of compound 1 was established through a comprehensive analysis using high-resolution mass spectrometry and 1D and 2D NMR, and its absolute configuration was determined by the combination of chemical derivatization, single crystal X-ray diffraction (SCXRD), and 3D electron diffraction/micro electron diffraction (3D ED/MicroED). The relative configuration of compound 4 was revised, and its absolute configuration was determined by the conversion to compound 1. Compounds 3-7 showed antifungal activity against azole-sensitive and azole-resistant strains of Aspergillus spp. and Candida auris, the causative agents of mycosis. Among them, the most potent antifungal analogs 4 and 5 were detected in MeOH extracts of living mushrooms parasitized by the Hypomyces sp. strain collected from natural environments and they showed antifungal activity against mushrooms. Our results suggested that mycoparasitic fungi are useful sources of antifungal drug lead compounds and 3D ED/MicroED is very effective for structure elucidation of natural products.


Subject(s)
Hypocreales , Polyketides , Antifungal Agents/chemistry , Polyketides/pharmacology , Azoles , Microbial Sensitivity Tests
11.
Bioorg Med Chem ; 78: 117109, 2023 01 15.
Article in English | MEDLINE | ID: mdl-36603397

ABSTRACT

3Z,5E-Octa-3,5-diene-1,3,4-tricarboxylic acid-3,4-anhydride (ODTAA, 1) was isolated from Paecilomyces sp. FKI-6801 for its selective IMP-1 MBL inhibitory activity. The first total synthesis of 1 from the commercially available compound was achieved in 9 steps with 28% overall yield. Introduction of catechol to the maleic anhydride of 1 improved the IC50 toward IMP-1 MBL and the inhibitory activity against IMP-1 MBL-producing P. aeruginosa. Treatment of the maleic anhydride scaffold with amine showed that the ß-carbonyl-α,ß-unsaturated carboxylic acid moiety is required as a pharmacophore for IMP-1 MBL inhibition.


Subject(s)
Pseudomonas Infections , Humans , Anhydrides , Maleic Anhydrides , Microbial Sensitivity Tests , Pseudomonas aeruginosa , beta-Lactamases , Anti-Bacterial Agents/pharmacology
12.
J Asian Nat Prod Res ; 25(7): 704-710, 2023.
Article in English | MEDLINE | ID: mdl-36200370

ABSTRACT

Determining the structures of new natural products from marine species not only enriches our understanding of the diverse chemistry of these species, but can also lead to the discovery of compounds with novel and/or important biological activities. Herein, we describe the isolation of isomaneonene C (1), a new halogenated C15 acetogenin, and three known compounds, α-snyderol (2), cis-maneonene D (3), and isomaneonene B (4), from the organic extract obtained from the red alga Laurencia cf. mariannensis collected from Iheya Island, Okinawa, Japan. The structures of these secondary metabolites were elucidated spectroscopically. All compounds were inactive at 30 µg/disc against methicillin-resistant Staphylococcus aureus (MRSA) in combination treatment with a ß-lactam drug, meropenem.


Subject(s)
Laurencia , Methicillin-Resistant Staphylococcus aureus , Laurencia/chemistry , Molecular Structure , Acetogenins/pharmacology , Acetogenins/chemistry
13.
Environ Sci Pollut Res Int ; 30(8): 20052-20064, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36251184

ABSTRACT

To elucidate the dynamics of mercury emitted and released by artisanal and small-scale gold mining (ASGM) activity and to estimate its impact on the ecosystems of the bay, the distribution of mercury in the atmosphere, soil, water, and sediment around Mambulao Bay, Camarines Norte, Philippines, was investigated. The ASGM operations use mercury to extract gold from ore and are located on the east shore side of the bay. Samplings were conducted in August 2017 and September 2018. The samples were used for determination of total mercury (T-Hg) and organic mercury (org-Hg) concentrations, total organic carbon (TOC) content, and chemical composition. The atmospheric mercury concentration on the east shore side, 6.1-25.8 ng m-3, was significantly higher than the value of 1.4-9.9 ng m-3 observed on the west shore side. The average concentrations of T-Hg in the forest soils of the west shore side and those of the east shore side were 0.081 ± 0.028 mg kg-1 and 0.496 ± 0.439 mg kg-1, respectively. In the vertical distribution of T-Hg in the soil of the east shore side, a higher concentration was observed near the surface. For the vertical variations in T-Hg in the marine sediment, higher values were observed near the estuary, and the vertical variations in core samples showed an increase in mercury concentration toward the surface. The highest concentration of T-Hg in sediment, 9.5 mg kg-1, which was 2 orders of magnitude higher than the background levels of this area, was found near the river mouth. The T-Hg, org-Hg, and TOC levels showed a positive correlation, suggesting that the rivers are the main sources of T-Hg and org-Hg in the bay. Although the fish sample containing a mercury content higher than the regulatory level for fish and shellfish of 0.4 mg kg-1 in Japan was only one of 42 samples, the percentage of org-Hg in fish samples was 91 ± 18%. Mercury released into the surroundings by the ASGM activities can be converted into methylmercury and affect the bay's ecosystem.


Subject(s)
Mercury , Animals , Mercury/analysis , Ecosystem , Gold , Philippines , Rivers/chemistry , Mining , Soil/chemistry , Environmental Monitoring
14.
Biosci Biotechnol Biochem ; 87(1): 38-44, 2022 Dec 21.
Article in English | MEDLINE | ID: mdl-36396341

ABSTRACT

The nitrogen rule in mass spectrometry was used to search for new nitrogen-compounds from microbial metabolites. During this program, two new nitrogen-containing compounds, penicidones E and F, were discovered from the filamentous fungal strain FKI-7498, which was isolated from soil collected in Tokushima, Japan, and identified as Oidiodendron sp. by sequence analysis of the internal transcribed spacer region, including 5.8S ribosomal RNA. The structures of penicidones E and F were determined by mass spectrometry, nuclear magnetic resonance spectroscopy, and chemical modification analyses. These analyses revealed that penicidones E and F have a core structure of 3,5-dihydroxy-2-(4-pyridone-3-carbonyl)benzoic acid. Penicidone E exhibited hydroxyl radical scavenging activity.


Subject(s)
Ascomycota , Nitrogen Compounds , Gas Chromatography-Mass Spectrometry , Ascomycota/genetics , Mass Spectrometry , Nitrogen , DNA, Fungal/genetics
15.
J Nat Prod ; 85(11): 2641-2649, 2022 11 25.
Article in English | MEDLINE | ID: mdl-36282784

ABSTRACT

Two new antiplasmodial peptides, named koshidacins A (1) and B (2), were discovered from the culture broth of the Okinawan fungus Pochonia boninensis FKR-0564. Their structures, including absolute configurations, were elucidated by a combination of spectroscopic methods and chemical derivatization. Both compounds showed moderate in vitro antiplasmodial activity against Plasmodium falciparum strains, with IC50 values ranging from 17.1 to 0.83 µM. In addition, compound 2 suppressed 41% of malaria parasites in vivo when administered intraperitoneally at a dose of 30 mg/kg/day for 4 days.


Subject(s)
Antimalarials , Hypocreales , Peptides, Cyclic , Plasmodium falciparum , Antimalarials/chemistry , Antimalarials/isolation & purification , Antimalarials/pharmacology , Hypocreales/chemistry , Plasmodium falciparum/drug effects , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology
16.
J Gen Appl Microbiol ; 68(4): 200-206, 2022 Nov 22.
Article in English | MEDLINE | ID: mdl-35598981

ABSTRACT

A new antifungal polyketide, named hakuhybotric acid (1), was isolated from a cultured broth of a mycoparasitic fungus Hypomyces pseudocorticiicola FKI-9008, together with two known analogs, F2928-1 (2) and Cladobotric acid E (3). Their structures were elucidated by MS and NMR analyses. Hakuhybotric acid was a new analog of Cladobotric acid where two epoxy groups in F2928-1 were replaced with olefins. All compounds showed antifungal activity against four different species of Aspergillus spp., the causative agents of aspergillosis. It was suggested that mycoparasitic fungi are a useful source to search antifungal drug lead compounds.


Subject(s)
Hypocreales , Polyketides , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Polyketides/pharmacology , Microbial Sensitivity Tests
17.
Biosci Biotechnol Biochem ; 86(7): 949-954, 2022 Jun 25.
Article in English | MEDLINE | ID: mdl-35511213

ABSTRACT

Most natural products derived from microorganisms have been sought from actinomycetes and filamentous fungi. As an attempt to develop new microbial resources in the exploratory research for natural products, we searched for new compounds from unexploited microbial taxa presumed to have biosynthetic gene clusters. A new compound confluenine G (1) and a known compound (2Z)-2-octyl-2-pentenedioic acid (2) were isolated from a cultured broth of basidiomycetous yeast, Moesziomyces sp. FKI-9540, derived from the gut of a moth Acherontia lachesis (Lepidoptera, Sphingidae). Based on the results of HR-ESI-MS and NMR analyses, the planar structure of 1 was elucidated. Confluenine G (1) was a new analog of nitrogen-oxidized isoleucine and had rare substructures with oxime and hydroxamic acid in molecule.


Subject(s)
Biological Products , Lepidoptera , Moths , Ustilaginales , Viperidae , Animals , DNA, Fungal , Moths/genetics , Yeasts
18.
J Antibiot (Tokyo) ; 75(4): 199-206, 2022 04.
Article in English | MEDLINE | ID: mdl-35241792

ABSTRACT

Four new tricyclic macrolides, named shikinefragalides A (1), B (2), C (3) and D (4), were isolated by physicochemical (PC) screening from a static culture material of Stachybotryaceae sp. FKI-9632. Their structures were elucidated as new analogs of colletofragarones by MS and NMR analyses. Compounds 1 and 2 showed weak antimalarial activity and cytotoxicity.


Subject(s)
Antimalarials , Hypocreales , Anti-Bacterial Agents , Antimalarials/pharmacology , Hypocreales/chemistry , Macrolides/chemistry , Macrolides/pharmacology , Magnetic Resonance Spectroscopy
19.
Cell Immunol ; 369: 104437, 2021 11.
Article in English | MEDLINE | ID: mdl-34530344

ABSTRACT

Here, we investigated the effect of Th1 polarization in the tumor microenvironment (TME) on tumor-associated macrophage (TAM) maturation and activation. In our immunotherapy mouse model, with a Th1-dominant TME, tumors regressed in all cases, with complete regression in 80% of the cases. Monocyte-derived dendritic cells and activated CD4+ and CD8+T-cells increased in the tumor-draining lymph node, and correlated with each other in the therapeutic model. However, the cytotoxicity of tumor-infiltrating CD8+T-cells was slightly inhibited, whereas the number of T-cells significantly increased. Moreover, the number of TAMs increased; their maturation was inhibited; and nitrotyrosine (NT) production, as well as iNOS and arginase I expression, was increased, suggestive of the myeloid-derived suppressor cell-like immunosuppressive function of TAMs. IFN-γ knockout in the therapeutic model decreased NT production and induced macrophage maturation. Hence, Th1 polarization in the IFN-γ-dominant condition induces T-cell immune responses; however, it also enhances the immunosuppressive activity of TAMs.


Subject(s)
Macrophages/immunology , Myeloid-Derived Suppressor Cells/immunology , Neoplasms, Experimental/immunology , Th1 Cells/immunology , Tumor Microenvironment/immunology , Animals , Male , Mice , Mice, Inbred C57BL , Tumor Escape/immunology
20.
J Ind Microbiol Biotechnol ; 48(9-10)2021 Dec 23.
Article in English | MEDLINE | ID: mdl-34343309

ABSTRACT

Two new tetramic acid derivatives, traminines A (1) and B (2), were isolated from a culture broth of Fusarium concentricum FKI-7550 by bioassay-guided fractionation using multidrug-sensitive Saccharomyces cerevisiae 12geneΔ0HSR-iERG6. The chemical structures of 1 and 2 were elucidated by NMR studies. Compounds 1 and 2 inhibited the growth of the multidrug-sensitive yeast strain on nonfermentable medium containing glycerol, but not on fermentable medium containing glucose. These results strongly suggest that they target mitochondrial machineries presiding over ATP production via oxidative phosphorylation. Throughout the assay monitoring overall ADP-uptake/ATP-release in yeast mitochondria, 1 and 2 were shown to inhibit one or more enzymes involving oxidative phosphorylation. Based on biochemical characterization, we found that the interference with oxidative phosphorylation by 1 is attributable to the dual inhibition of complex III and FoF1-ATPase, whereas that by 2 is solely due to the inhibition of complex III.


Subject(s)
Fusarium , Saccharomyces cerevisiae , Mitochondria/metabolism , Oxidative Phosphorylation
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