Retinestatin, a Polyol Polyketide from a Termite Nest-Derived Streptomyces sp.

A new polyol polyketide, named retinestatin (1), was obtained and characterized from the culture of a Streptomyces strain, which was isolated from a subterranean nest of the termite Reticulitermes speratus kyushuensis Morimoto. The planar structure of 1 was elucidated on the basis of the cumulative analysis of ultraviolet, infrared, mass spectrometry, and nuclear magnetic resonance spectroscopic data. The absolute configuration of 1 at 12 chiral centers was successfully assigned by employing a J-based configuration analysis in combination with ROESY correlations, a quantum mechanics-based computational approach to calculate NMR chemical shifts, and a 3 min flash esterification by Mosher's reagents followed by NMR analysis. Biological evaluation of retinestatin (1) using an in vitro model of Parkinson's disease revealed that 1 protected SH-SY5Y dopaminergic cells from MPP+-induced cytotoxicity, indicating its neuroprotective effects.

Expanding the Chemical Diversity of Grisechelins via Heterologous Expression.

Thiazole scaffold-based small molecules exhibit a range of biological activities and play important roles in drug discovery. Based on bioinformatics analysis, a putative biosynthetic gene cluster (BGC) for thiazole-containing compounds was identified from Streptomyces sp. SCSIO 40020. Heterologous expression of this BGC led to the production of eight new thiazole-containing compounds, grisechelins E, F, and I-N (1, 2, 5-10), and two quinoline derivatives, grisechelins G and H (3 and 4). The structures of 1-10, including their absolute configurations, were elucidated by HRESIMS, NMR spectroscopic data, ECD calculations, and single-crystal X-ray diffraction analysis. Grisechelin F (2) is a unique derivative, distinguished by the presence of a salicylic acid moiety. The biosynthetic pathway for 2 was proposed based on bioinformatics analysis and in vivo gene knockout experiments. Grisechelin E (1) displayed moderate antimycobacterial activity against Mycobacterium tuberculosis H37Ra (MIC of 8 µg mL-1).

Diverse ansamycin derivatives from the marine-derived Streptomyces sp. ZYX-F-97 and their antibacterial activities.

Four new ansamycin derivatives, named 1,19-epithio-geldanamycin A (1), 17-demethoxylherbimycin H (2), herbimycin M (3), and seco-geldanamycin B (4), together with eight known ansamycin analogues (5-12) were isolated from the solid fermentation of marine-derived actinomycete Streptomyces sp. ZYX-F-97. The structures of new compounds were elucidated by extensive spectroscopic analysis as well as nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculations. All the compounds were assayed for their antibacterial activity. Among them, compounds 4, 8, and 12 exhibited remarkable inhibition against Listeria monocytogenes with minimum inhibitory concentrations (MIC) values ranging from 8 µg·mL-1 to 64 µg·mL-1, and displayed moderate inhibition against methicillin-resistant Staphylococcus aureus (MRSA) with MIC value of 64 µg·mL-1. Compounds 4, 8, 9, and 12 showed moderate inhibition activities against both Staphylococcus aureus and Bacillus subtilis with MIC values ranging from 32 µg·mL-1 to 128 µg·mL-1.

New Alpiniamide-Type Polyketide with Antibiofilm Activities from the Marine-Derived Streptomyces sp. ZS-A65.

Two new alpiniamide-type polyketides, alpiniamides H-I (1-2), in addition to four recognized compounds, were discovered in Streptomyces sp. ZSA65 derived from the marine sediments. The planar structure and absolute configuration of alpiniamides H-I were elucidated using a combination of 1D, 2D NMR, HRESIMS data analysis, Mosher's method and ECD calculations. The antibiofilm and antibacterial activities against P. aeruginosa were evaluated using the microdilution method. Notably, Compound 2 exhibited strong antibiofilm property.

Structurally Diverse Macrolactams from an Antarctic Streptomyces Species.

Twelve new polyenic macrolactams, cyclamenols G-R (1 and 3-13), together with the known analogue cyclamenol A (2), were isolated from Streptomyces sp. OUCMDZ-4348. Their structures were elucidated by spectroscopic analysis, quantum chemical calculations, chemical derivatizations, and Mosher's methods. The sequenced genome of OUCMDZ-4348 revealed the putative biosynthetic gene cluster of cyclamenols. It was proposed that the polycyclic natural products, cyclamenols H-R, might be formed from cyclamenols A and G through nonenzymatic intramolecular cycloadditions and oxidative cyclizations.

Structures, Biosynthesis, and Bioactivity of Oligomycins from the Marine-Derived Streptomyces sp. FXY-T5.

Oligomycins are potent antifungal and antitumor agents. Mass spectrometry (MS)- and nuclear magnetic resonance (NMR)-based metabolomic fingerprinting analysis of marine-derived actinomycetes in our in-house library provided an oligomycin-producing strain, Streptomyces sp. FXY-T5. Chemical investigation led to the discovery of five new oligomycins, 24-lumooligomycin B (1), 4-lumooligomycin B (2), 6-lumooligomycin B (3), 40-homooligomycin B (4), and 15-hydroxy-oligomycin B (5), together with seven biosynthetically related known derivatives. Their structures were assigned by MS, NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. The biosynthesis pathway of oligomycins was first proposed based on the analysis of a type I modular polyketide synthase (PKS) system and targeted gene disruption. As expected, the isolated oligomycins showed significant antiagricultural fungal pathogen activity and antiproliferative properties from which the possible structure-activity relationships were first suggested. More importantly, oligomycins induced significant G1-phase cell cycle arrest on cancer cells and significantly attenuated their Cyclin D1 and PCNA expression through a ß-catenin signaling pathway.

Cytotoxic and Antifungal Staurosporine Derivatives from Marine-Derived Actinomycete Streptomyces sp. ZS-A121.

A novel staurosporine derivate, streptomholyrine A (1), along with 6 known compounds were identified from the rice-based solid fermentation of marine-derived Streptomyces sp. ZS-A121. The planar structure and absolute configuration of streptomholyrine A were elucidated using a combination of 1D, 2D NMR, HRESIMS data analysis, chemical transformation, ECD and NMR calculations. Screening of all these compounds revealed their cytotoxic activity against HCT-116 cell lines, with IC50 values ranging from 0.012 to 11.67 µM, except for the known 1H-indole-3-hydroxyacetyl, which showed no inhibition activity. Furthermore, streptomholyrine A, along with two known staurosporine derivatives, k252d and staurosporine, exhibited activities against Candida albicans, with MICs of 12.5, 25.0 and 50.0 µg/ml, respectively.

Mimicking Nonribosomal Peptides from the Marine Actinomycete Streptomyces sp. H-KF8 Leads to Antimicrobial Peptides.

Microorganisms within the marine environment have been shown to be very effective sources of naturally produced antimicrobial peptides (AMPs). Several nonribosomal peptides were identified based on genome mining predictions of Streptomyces sp. H-KF8, a marine Actinomycetota isolated from a remote Northern Chilean Patagonian fjord. Based on these predictions, a series of eight peptides, including cyclic peptides, were designed and chemically synthesized. Six of these peptides showed antimicrobial activity. Mode of action studies suggest that two of these peptides potentially act on the cell membrane via a novel mechanism allowing the passage of small ions, resulting in the dissipation of the membrane potential. This study shows that though structurally similar peptides, determined by NMR spectroscopy, the incorporation of small sequence mutations results in a dramatic influence on their bioactivity including mode of action. The qualified hit sequence can serve as a basis for more potent AMPs in future studies.

Anti-MRSA Dimeric and Brominated Phenyltetracenoids Produced by Streptomyces morookaense SC1169.

Eleven new phenyltetracenoid polyketides, streptovertimycins U (1) and V (2), 14-bromo-streptovertidione (3), streptovertimycins W-Y (4-6), and streptovertimycins Z1-Z5 (7-11), together with the known congeners fasamycins R (12) and S (13) and accramycins A (14) and B (15), were isolated from the NaBr-supplemented rice-grown cultures of Streptomyces morookaense SC1169. Their structures were elucidated by extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and theoretical computations of ECD spectra. Compounds 1 and 2 are methylene-bridged dimers of accramycin A, and compounds 3 and 7-11 are brominated fasamycin congeners. Compounds 5 and 8-14 exhibited activity against the drug-resistant bacteria MRSA and VRE (MIC = 0.6-5.0 µg/mL), and the dimer 1 displayed activity against MRSA (MIC = 2.5 µg/mL). Compounds 6-15 showed cytotoxicity against the human carcinoma A549, HeLa, HepG2, and MCF-7 cells in the IC50 range between 1.7 and 9.2 µM.

Kueishanamides A and B from the Hydrothermal Vent Sediment Derived Streptomyces sp. WU20.

Marine actinomycetes are known for their production of remarkable organic molecules, particularly those featuring polyoxygenated long-chain backbones. Determining the absolute configurations of these compounds remains a challenging task even today. In this study, we successfully established the planar structures and absolute configurations of two highly flexible amide alkaloids from Streptomyces sp. WU20: kueishanamides A (1) and B (2). These compounds possess a C13 linear backbone and each contains five stereogenic carbon centers. Our approach involved a combination of spectroscopic and computational methods, including J-based configurational analysis and VCD calculations, ensuring the unambiguous determination of their configurations. Kueishanamide A (1) and kueishanamide B (2) showed moderate antifungal activity against pathogenic fungus Crytococcus neoformans, with MIC values of 25 µg/mL each.

Haneummycin, a new 22-membered macrolide lactam antibiotic, produced by marine-derived Streptomyces sp. KM77-8.

A new antibiotic named haneummycin (1) was isolated from a culture broth of marine-derived Streptomyces sp. KM77-8 by solvent extraction and HPLC using a C4 column. The structure of 1 was elucidated including relative stereochemistry as a new 22-membered macrolide lactam associated with a cyclopentanone and three sugars by various spectroscopic analyses, such as MS and NMR. Compound 1 displayed significant antibacterial activities against Gram-positive bacteria including vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) with both MIC values of 8.0 µg ml-1.

Structurally Diverse Metabolites from the Marine-Derived Streptomyces sp. DS-27 Based on Two Different Culture Conditions.

Nine new compounds, including streptothiomycin A-E (1-5), two cyclopentenones (6, 7), one α-pyrone (8), wailupemycin Q (20), along with sixteen known compounds were identified from a rhizosphere strain Streptomyces sp. DS-27 derived from the marine cordgrass Spartina alterniflora under two different culture conditions. All of the structures were elucidated by extensive analysis of 1D/2D NMR and HR-ESI-MS data. The absolute configurations were determined by NOESY analysis, ECD, specific rotation and GIAO NMR calculations, and DP4+ probability analysis. Bioactivity investigation showed that compounds 5 and 7 exhibited significant inhibitory effects on LPS-induced NO production in a dose-dependent manner, which indicates their anti-inflammatory potential.

Turonicin A, an Antifungal Linear Polyene Polyketide from an Australian Streptomyces sp.

Turonicin A (1) was isolated from Streptomyces sp. MST-123921, which was recovered from soil collected on the banks of the Turon River in New South Wales, Australia. Turonicin A (1) is an amphoteric linear polyene polyketide featuring independent pentaene and tetraenone chromophores and is structurally related to linearmycins A-C (2-4). The structure of 1 was determined by detailed spectroscopic analysis and comparison to literature data. Bioinformatic analysis of the linearmycin biosynthetic gene cluster also allowed the previously unresolved absolute stereostructures of 2-4 to be elucidated. Turonicin A (1) exhibited very potent activity against the fungi Candida albicans (MIC 0.0031 µg/mL, 2.7 nM) and Saccharomyces cerevisiae (MIC 0.0008 µg/mL, 0.7 nM), moderate activity against the bacteria Bacillus subtilis (MIC 0.097 µg/mL, 85 nM) and Staphylococcus aureus (MIC 0.39 µg/mL, 340 nM), and no cytotoxicity against human fibroblasts, making it an attractive candidate for further development as a potential next-generation antibiotic scaffold.

Ravidomycin Analogs from Streptomyces sp. Exhibit Altered Antimicrobial and Cytotoxic Selectivity.

Six new ravidomycin analogs (1-4, 6, and 7) were isolated from Streptomyces sp. Am59 using UV- and LCMS-guided separation based on Global Natural Products Social (GNPS) molecular networking analysis. Furthermore, we isolated fucomycin V (9), which possesses the same chromophore as ravidomycin but features a d-fucopyranose instead of d-ravidosamine. This is the first report of 9 as a natural product. Four new analogs (10-13) of 9 were also isolated. The structures were elucidated by combined spectroscopic and computational methods. We also found an inconsistency with the published [α]D25 of deacetylravidomycin, which is reported to have a (-) sign. Instead, we observed a (+) specific rotation for the reported absolute configuration of deacetylravidomycin (containing d-ravidosamine). We confirmed the positive sign by reisolating deacetylravidomycin from S. ravidus and by deacetylating ravidomycin. Finally, antibacterial, antifungal, and cytotoxicity activities were determined for the compounds. Compared to deacetylravidomycin, the compounds 4-6, 9, 11, and 12 exhibited greater antibacterial selectivity.

Protein Profiling of Aedes aegypti Treated with Streptomyces sp. KSF103 Ethyl Acetate Extract Reveals Potential Insecticidal Targets and Metabolic Pathways.

The insecticidal activity of Streptomyces sp. KSF103 ethyl acetate (EA) extract against mosquitoes is known; however, the underlying mechanism behind this activity remains elusive. In this study, liquid chromatography with tandem mass spectrometry (LC-MS/MS) was employed to investigate changes in the protein profile of Aedes aegypti larvae and adults treated with lethal concentrations of 50 (LC50) EA extract. By comparing the treated and untreated mosquitoes, this study aimed to identify proteins or pathways that exhibit alterations, potentially serving as targets for future insecticide development. Treatment with a lethal concentration of EA extract upregulated 15 proteins in larvae, while in adults, 16 proteins were upregulated, and two proteins were downregulated. These proteins were associated with metabolism, protein regulation/degradation, energy production, cellular organization and structure, enzyme activity, and catalysis, as well as calcium ion transport and homeostasis. Notably, ATP synthase, fructose-bisphosphate aldolase (FBA), and ATP citrate synthase were significantly expressed in both groups. Gene ontology analysis indicated a focus on energy metabolic processes. Molecular docking revealed a strong interaction between dodemorph, selagine (compounds from the EA extract), and FBA, suggesting FBA as a potential protein target for insecticide development. Further studies such as Western blot and transcriptomic analyses are warranted to validate the findings.

Identification of Obscurolide-Type Metabolites and Antifungal Metabolites from the Termite-Associated Streptomyces neopeptinius BYF101.

Streptomyces spp. are well-known symbiotic microorganisms that produce antimicrobial metabolites against various pathogens. We isolated actinomycetes from the body surface of the termite Odontotermes formosanus and identified it as Streptomyces neopeptinius BYF101 based on 16S rRNA phylogenetic analysis. Chemical analysis of the cultures of termite-associated S. neopeptinius BYF101 via HR-MS2 and GNPS analyses enabled the isolation and identification of 20 metabolites, including the unreported obscurolide-type metabolites (1-3). The chemical structures of unreported compounds (1-3) were elucidated using HR-ESI-MS and 1D and 2D NMR analysis, and their absolute configurations were determined via chemical reactions followed by the application of competing enantioselective acylation (CEA) and computational methods for ECD and DP4+ probability calculation. The isolated compounds (1-20) were tested to determine their antifungal activity against two human fungal pathogens, Candida albicans and Cryptococcus neoformans. Among the compounds tested, indole-3-carboxylic acid (9) displayed antifungal activity against C. neoformans, with an MIC value of 12 µg/mL.

Rubiflavin G, photorubiflavin G, and photorubiflavin E: Novel pluramycin derivatives from Streptomyces sp. W2061 and their anticancer activity against breast cancer cells.

The pluramycin family of antibiotics comprises angucycline compounds derived from actinomycetes that possess anticancer and antibacterial properties. Pluramycins are structurally characterized by two aminoglycosides linked by a carbon-carbon bond next to the γ-pyrone angucycline backbone. Kidamycins (3, 4) and rubiflavins (6-9) were screened through liquid chromatography-mass spectrometry analysis of the crude extracts of Streptomyces sp. W2061, which was cultured in complex media under phosphate-limiting conditions. Newly isolated rubiflavin G (7) and photoactivated compounds (8, 9) were characterized using exhaustive 1D and 2D nuclear magnetic resonance analysis. The cytotoxicity of kidamycin (3), photokidamycin (4), and photorubiflavin G (8) was determined using two human breast cancer cell lines-MCF7 and MDA-MB-231. Compared to MCF7 cells, MDA-MB-231 cells were more sensitive to the active compounds, and photokidamycin (4) considerably inhibited MCF7 and MDA-MB-231 cell growth (IC50 = 3.51 and 0.66 µM, respectively).

Iseoic acids and bisiseoate: three new naphthohydroquinone/naphthoquinone-class metabolites from a coral-derived Streptomyces.

Two new naphthohydroquinone derivatives designated iseoic acids A (1) and B (2) and a new symmetrical glycerol bisester of naphthoquinonepropanoic acid designated bisiseoate (3) were isolated from the culture extract of a marine-derived actinomycete Streptomyces sp. DC4-5. The structures of 1-3 were determined by analyzing one- and two-dimensional NMR data and MS analytical data. The absolute configurations were determined by NOESY analysis and the phenylglycine methyl ester (PGME) method for 1 and by considering the structural similarity and biosynthesis for 2 and 3. Compound 3 exhibited modest cytotoxicity against P388 murine leukemia cells with an IC50 value of 19 µM.

Discovery and Biosynthetic Studies of a Highly Reduced Cinnamoyl Lipid, Tripmycin A, from an Endophytic Streptomyces sp.

A Tripterygium wilfordii endophyte, Streptomyces sp. CB04723, was shown to produce an unusually highly reduced cytotoxic cinnamoyl lipid, tripmycin A (1). Structure-activity relationship studies revealed that both the cinnamyl moiety and the saturated fatty acid side chain are indispensable to the over 400-fold cytotoxicity improvement of 1 against the triple-negative breast cancer cell line MDA-MB-231 compared to 5-(2-methylphenyl)-4-pentenoic acid (2). Bioinformatical analysis, gene inactivation, and overexpression revealed that Hxs15 most likely acted as an enoyl reductase and was involved with the side chain reduction of 1, which provides a new insight into the biosynthesis of cinnamoyl lipids.

Jejucarbosides B-E, Chlorinated Cycloaromatized Enediynes, from a Marine Streptomyces sp.

Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B-E (1-4), were discovered together with previously-identified jejucarboside A from a marine actinomycete strain. Compounds 1-4 were identified as new chlorinated cyclopenta[a]indene glycosides based on 1D and 2D nuclear magnetic resonance, high-resolution mass spectrometry, and circular dichroism (CD) spectra. Jejucarbosides B and E bear a carbonate functional group whereas jejucarbosides C and D are variants possessing 1,2-diol by losing the carbonate functionality. It is proposed that the production of 1-4 occurs via Bergman cycloaromatization capturing Cl- and H+ in the alternative positions of a p-benzyne intermediate derived from a 9-membered enediyne core. Jejucarboside E (4) displayed significant cytotoxicity against human cancer cell lines including SNU-638, SK-HEP-1, A549, HCT116, and MDA-MB-231, with IC50 values of 0.31, 0.40, 0.25, 0.29, and 0.48 µM, respectively, while jejucarbosides B-D (1-3) showed moderate or no cytotoxic effects.