Search Results (20)

Microorganisms from poorly explored environments are promising sources for the development of novel drugs. In our continuous efforts to screen for mangrove actinomycetes that produce metabolites with potential pharmaceutical applications, Streptomyces sp. Y009 was isolated from mangrove sediments in Guangxi, China. The phenotypic, physiological, biochemical, and phylogenetic characteristics of this strain were investigated. Analysis of phylogenetic and 16S rRNA gene sequences showed that it had the highest sequence similarity to Streptomyces thermolilacinus NBRC 14274 (98.95%). Further, the Y009 extract exhibited antioxidant activity, as indicated by DPPH and superoxide dismutase assays. The extract showed broad-spectrum and potent anticancer potential against six human cancer cell lines, with IC₅₀ values ranging from 5.61 to 72.15 μg/mL. Furthermore, the selectivity index (SI) demonstrated that the Y009 extract exhibited less toxicity toward normal cell lines in comparison to the lung cancer cell line (A549) and hepatoma cell line (HepG2). GC–MS analysis revealed that the extract contained some biologically important secondary metabolites, mainly cyclic dipeptides and esters, which might be responsible for the antioxidant and anticancer properties. 3-Isobutylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione (28.32%) was the major chemical compound available in the extract. The effect on cancer cells was then confirmed using nuclear staining and in silico docking. This study suggests that further exploration of the bioactive compounds of the newly isolated strain may be a promising approach for the development of novel chemopreventive drugs. Full article

It is important to improve the production of bioactive secondary products for drug development. The Escherichia coli—Streptomyces shuttle vector pSET152 and its derived vector pIB139 containing a strong constitutive promoter ermEp* are commonly used as integrative vectors in actinomycetes. Four new integrative vectors carrying the strong constitutive promoter kasOp*, hrdBp, SCO5768p, and SP44, respectively, were constructed and proven to be functional in different mangrove-derived Streptomyces host strains by using kanamycin resistance gene neo as a reporter. Some biosynthetic genes of elaiophylins, azalomycin Fs, and armeniaspirols were selected and inserted into these vectors to overexpress in their producers including Streptomyces sp. 219807, Streptomyces sp. 211726, and S. armeniacus DSM 43125, resulting in an approximately 1.1–1.4-fold enhancement of the antibiotic yields. Full article

Mangrove-derived actinomycetes represent a rich source of novel bioactive natural products in drug discovery. In this study, four new polyene macrolide antibiotics antifungalmycin B-E (1–4), along with seven known analogs (5–11), were isolated from the fermentation broth of the mangrove strain Streptomyces hiroshimensis GXIMD 06359. All compounds from this strain were purified using semi-preparative HPLC and Sephadex LH-20 gel filtration while following an antifungal activity-guided fractionation. Their structures were elucidated through spectroscopic techniques including UV, HR-ESI-MS, and NMR. These compounds exhibited broad-spectrum antifungal activity against Talaromyces marneffei with minimum inhibitory concentration (MIC) values being in the range of 2–128 μg/mL except compound 2. This is the first report of polyene derivatives produced by S. hiroshimensis as bioactive compounds against T. marneffei. In vitro studies showed that compound 1 exerted a significantly stronger antifungal activity against T. marneffei than other new compounds, and the antifungal mechanism of compound 1 may be related to the disrupted cell membrane, which causes mitochondrial dysfunction, resulting in leakage of intracellular biological components, and subsequently, cell death. Taken together, this study provides a basis for compound 1 preventing and controlling talaromycosis. Full article

α-Glucosidase (AGS) inhibitors have been regarded as an ideal target for the management of type 2 diabetes mellitus (T2DM) since they can maintain an acceptable blood glucose level by delaying the digestion of carbohydrates and diminishing the absorption of monosaccharides. In the process of our endeavor in mining AGS inhibitors from natural sources, the culture broth of two mangrove-derived actinomycetes Streptomyces sp. WHUA03267 and Streptomyces sp. WHUA03072 exhibited an apparent inhibitory activity against AGS. A subsequent chemical investigation into the two extracts furnished 28 secondary metabolites that were identified by spectroscopic methods as two previously undescribed linear polyketides 1–2, four benzenoid ansamycins 3–6, fourteen cyclodipeptides 7–18, one prenylated indole derivative 19, two fusicoccane-type diterpenoids 20–21, two hydroxamate siderophore 22–23, and five others 24–28. Among all of the isolates, 11 and 24 were obtained from actinomycetes for the first time, while 20–21 had never been reported to occur in a marine-derived microorganism previously. In the in vitro AGS inhibitory assay, compounds 3, 8, 9, 11, 14, 16, and 17 exhibited potent to moderate activity with IC₅₀ values ranging from 35.76 ± 0.40 to 164.5 ± 15.5 μM, as compared with acarbose (IC₅₀ = 422.3 ± 8.4 μM). The AGS inhibitory activity of 3, 9, 14, 16, and 17 was reported for the first time. In particular, autolytimycin (3) represented the first ansamycin derivative reported to possess the AGS inhibitory activity. Kinetics analysis and molecular docking were performed to determine the inhibition types and binding modes of these inhibitors, respectively. In the MTT assay, 3, 8, 9, 11, 14, 16, and 17 exhibited no apparent cytotoxicity to the human normal hepatocyte (LO2) cells, suggesting satisfactory safety of these AGS inhibitors. Full article

Mangrove sediment ecosystems in the coastal areas of the Yucatan peninsula are unique environments, influenced by their karstic origin and connection with the world’s largest underground river. The microbial communities residing in these sediments are influenced by the presence of mangrove roots and the trading chemistry for communication between sediment bacteria and plant roots can be targeted for secondary metabolite research. To explore the secondary metabolite production potential of microbial community members in mangrove sediments at the “El Palmar” natural reserve in Sisal, Yucatan, a combined meta-omics approach was applied. The effects of a cultivation medium reported to select for actinomycetes within mangrove sediments’ microbial communities was also analyzed. The metabolome of the microbial communities was analyzed by high-resolution liquid chromatography-tandem mass spectrometry, and molecular networking analysis was used to investigate if known natural products and their variants were present. Metagenomic results suggest that the sediments from “El Palmar” harbor a stable bacterial community independently of their distance from mangrove tree roots. An unexpected decrease in the observed abundance of actinomycetes present in the communities occurred when an antibiotic-amended medium considered to be actinomycete-selective was applied for a 30-day period. However, the use of this antibiotic-amended medium also enhanced production of secondary metabolites within the microbial community present relative to the water control, suggesting the treatment selected for antibiotic-resistant bacteria capable of producing a higher number of secondary metabolites. Secondary metabolite mining of “El Palmar” microbial community metagenomes identified polyketide synthase and non-ribosomal peptide synthetases’ biosynthetic genes in all analyzed metagenomes. The presence of these genes correlated with the annotation of several secondary metabolites from the Global Natural Product Social Molecular Networking database. These results highlight the biotechnological potential of the microbial communities from “El Palmar”, and show the impact selective media had on the composition of communities of actinobacteria. Full article

The mangrove-sediment-derived actinomycete strain Streptomyces psammoticus SCSIO NS126 was found to have productive piericidin metabolites featuring anti-renal cell carcinoma activities. In this study, in order to explore more diverse piericidin derivatives, and therefore to discover superior anti-tumor lead compounds, the NS126 strain was further fermented at a 300-L scale under optimized fermentation conditions. As a result, eight new minor piericidin derivatives (piericidins L-R (1–7) and 11-demethyl-glucopiericidin A (8)) were obtained, along with glucopiericidin B (9). The new structures including absolute configurations were determined by spectroscopic methods coupled with experimental and calculated electronic circular dichroism. We also proposed plausible biosynthetic pathways for these unusual post-modified piericidins. Compounds 1 and 6 showed selective cytotoxic activities against OS-RC-2 cells, and 2–5 exhibited potent cytotoxicity against HL-60 cells, with IC₅₀ values lower than 0.1 μM. The new piericidin glycoside 8 was cytotoxic against ACHN, HL-60 and K562, with IC₅₀ values of 2.3, 1.3 and 5.5 μM, respectively. The ability to arrest the cell cycle and cell apoptosis effects induced by 1 and 6 in OS-RC-2 cells, 2 in HL-60 cells, and 8 in ACHN cells were then further investigated. This study enriched the structural diversity of piericidin derivatives and confirmed that piericidins deserve further investigations as promising anti-tumor agents. Full article

The mangrove ecosystem is a rich resource for the discovery of actinomycetes with potential applications in pharmaceutical science. Besides the genus Streptomyces, Micromonospora is also a source of new bioactive agents. We screened Micromonospora from the rhizosphere soil of mangrove plants in Fujian province, China, and 51 strains were obtained. Among them, the extracts of 12 isolates inhibited the growth of human lung carcinoma A549 cells. Strain 110B exhibited better cytotoxic activity, and its bioactive constituents were investigated. Consequently, three new isoflavonoid glycosides, daidzein-4′-(2-deoxy-α-l-fucopyranoside) (1), daidzein-7-(2-deoxy-α-l-fucopyranoside) (2), and daidzein-4′,7-di-(2-deoxy-α-l-fucopyranoside) (3) were isolated from the fermentation broth of strain 110B. The structures of the new compounds were determined by spectroscopic methods, including 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESIMS). The result of medium-changing experiments implicated that these new compounds were microbial biotransformation products of strain M. aurantiaca 110B. The three compounds displayed moderate cytotoxic activity to the human lung carcinoma cell line A549, hepatocellular liver carcinoma cell line HepG2, and the human colon tumor cell line HCT116, whereas none of them showed antifungal or antibacterial activities. Full article

Bioactive secondary metabolites from Streptomycetes are important sources of lead compounds in current drug development. Streptomyces costaricanus SCSIO ZS0073, a mangrove-derived actinomycete, produces actinomycin D, a clinically used therapeutic for Wilm’s tumor of the kidney, trophoblastic tumors and rhabdomyosarcoma. In this work, we identified the actinomycin biosynthetic gene cluster (BGC) acn by detailed analyses of the S. costaricanus SCSIO ZS0073 genome. This organism produces actinomycin D with a titer of ~69.8 μg mL⁻¹ along with traces of actinomycin X_oβ. The acn cluster localized to a 39.8 kb length region consisting of 25 open reading frames (ORFs), including a set of four genes that drive the construction of the 4-methyl-3-hydroxy-anthranilic acid (4-MHA) precursor and three non-ribosomal peptide synthetases (NRPSs) that generate the 4-MHA pentapeptide semi-lactone, which, upon dimerization, affords final actinomycin D. Furthermore, the acn cluster contains four positive regulatory genes acnWU4RO, which were identified by in vivo gene inactivation studies. Our data provide insights into the genetic characteristics of this new mangrove-derived actinomycin D bioproducer, enabling future metabolic engineering campaigns to improve both titers and the structural diversities possible for actinomycin D and related analogues. Full article

Four new ansamycins, named divergolides T–W (1–4), along with two known analogs were isolated from the fermentation broth of the mangrove-derived actinomycete Streptomyces sp. KFD18. The structures of the compounds, including the absolute configurations of their stereogenic carbons, were determined by spectroscopic data and single-crystal X-ray diffraction analysis. Compounds 1–4 showed cytotoxic activity against the human gastric cancer cell line SGC-7901, the human leukemic cell line K562, the HeLa cell line, and the human lung carcinoma cell line A549, with 1 being the most active while compounds 5 and 6 were inactive against all the tested cell lines. Compounds 1 and 3 showed very potent and specific cytotoxic activities (IC₅₀ 2.8 and 4.7 µM, respectively) against the SGC-7901 cells. Further, the apoptosis-inducing effect of 1 and 3 against SGC-7901 cells was demonstrated by two kinds of staining methods for the first time. Full article

Global public health faces a desperate situation, due to the lack of effective antibiotics. Coordinated steps need to be taken, worldwide, to rectify this situation and protect the advances in modern medicine made over the last 100 years. Work at Japan’s Kitasato Institute has been in the vanguard of many such advances, and work is being proactively tailored to promote the discovery of urgently needed antimicrobials. Efforts are being concentrated on actinomycetes, the proven source of most modern antibiotics. We devised a novel physicochemical screening mechanism, whereby simple physico-chemical properties, in conjunction with related detection methods, such as LC/MS, LC/UV, and polarity, could be used to identify or predict new compounds in a culture broth, simply by comparing results with existing databases. New compounds are isolated, purified, and their structure determined before being tested for any bioactivity. We used lyophilized actinomycete strains from the Kitasato Microbial Library, most more than 35 years old, and found 330 strains were producers of useful bioactive substances. We also tested organisms found in fresh samples collected in the complex environments from around plant roots, as well as from sediments of mangrove forests and oceans, resulting in the discovery of 36 novel compounds from 11 actinomycete strains. A compound, designated iminimycin, containing an iminium ion in the structure was discovered from the culture broth of Streptomyces griseus OS-3601, which had been stored for a long time as a streptomycin-producing strain. This represented the first iminium ion discovery in actinomycetes. Compounds with a cyclopentadecane skeleton containing 5,6-dihydro-4-hydroxyl-2-pyrone ring and tetrahydrofuran ring, designated mangromicins, were isolated from the culture broth of Lechevalieria aerocolonigenes K10-0216 obtained from sediment in a mangrove forest. These structures are extremely unique among natural compounds. From the same culture broth, new steroid compounds, named K10-0216 KA and KB, and other new compounds having a thiazole and a pyridine ring, named pyrizomicin A and B, were discovered. New substances can be found from actinomycetes that have been exhaustively studied. Novel compounds with different skeletons can be found from a single broth of one strain. The sought after new antibiotics will arise from continued exploitation of the actinomycetes, especially rare actinomycetes. Work on new organisms and samples should be augmented by re-examination of known actinomycetes already in storage. New research should also be carried out on the manipulation of culture media, thereby stimulating actinomycete strains to produce novel chemicals. The establishment of wide-ranging international research collaborations will facilitate and expedite the efficient and timely discovery and provision of bioactive compounds to help maintain and promote advances in global public health. Full article

An actinomycete strain (H12-15) isolated from a sea sediment in a mangrove district was identified as Streptomyces antibioticus on the basis of 16S rDNA gene sequence analysis as well as the investigation of its morphological, physiological, and biochemical characteristics. Two novel benzamido nonacyclic dilactones, namely neoantimycins A (1) and B (2), together with the known antimycins A_1ab (3a,b), A_2a (4), and A₉ (5), were isolated from the culture broth of this strain. Compounds 1 and 2 are the first natural modified ATNs with an unusual benzamide unit. The structures of these new compounds, including their absolute configuration, were established on the basis of HRMS, NMR spectroscopic data, and quantum chemical ECD calculations. Their cytotoxicities against human breast adenocarcinoma cell line MCF-7, the human glioblastoma cell line SF-268, and the human lung cancer cell line NCI-H460 were also tested. All compounds exhibited mild cytotoxic activity. However, Compounds 1 and 2 showed no activity against C. albicans at the test concentration of 1 mg/mL via paper disc diffusion, while the known antimycins showed obvious antifungal activity. Full article

During our search for interesting bioactive secondary metabolites from mangrove actinomycetes, the strain Streptomyces sp. 219807 which produced a high elaiophylin yield of 4486 mg/L was obtained. A new elaiophylin derivative, halichoblelide D (1), along with seven known analogues 2–8 was isolated and identified from the culture broth. Their chemical structures were determined by detailed analysis of 1D and 2D NMR and HRMS data. The absolute configuration of halichoblelide D (1) was confirmed by comparing the CD spectrum with those of the reported analogues. Compounds 1–7 exhibited potent cytotoxic activities against HeLa and MCF-7 cells with IC₅₀ values ranging from 0.19 to 2.12 μM. Full article

An actinomycete strain, H41-59, isolated from sea sediment in a mangrove district, was identified as Streptomyces anandii on the basis of 16S rDNA gene sequence analysis as well as the investigation of its morphological, physiological and biochemical characteristics. Three new ergosterols, ananstreps A–C (1–3), along with ten known ones (4–13), were isolated from the culture broth of this strain. The gross structures of these new compounds were elucidated on the basis of extensive analysis of spectroscopic data, including HR-ESI-MS, and NMR. The cytotoxicities of these isolates against human breast adenocarcinoma cell line MCF-7, human glioblastoma cell line SF-268, and human lung cancer cell line NCI-H460 and their antibacterial activities in inhibiting the growth of Candida albicans and some other pathogenic microorganisms were tested. Compounds 3–8, 10 and 11 displayed cytotoxicity with IC₅₀ values in a range from 13.0 to 27.8 μg/mL. However, all the tested compounds showed no activity on C. albicans and other bacteria at the test concentration of 1 mg/mL with the paper disc diffusion method. Full article

We report the structural characterization of a new pyrazinone analogue; butrepyrazinone, which was isolated from a new actinomycete strain Verrucosispora sp. K51G recovered from Ghanaian mangrove river sediment. Spectroscopy-guided fractionation led to the isolation of a compound from the fermentation culture and a combination of NMR spectroscopy, high-resolution mass spectrometry and computer-aided calculations revealed that butrepyrazinone (10) possesses an unusual methylation pattern on the pyrazinone ring. Butrepyrazinone (10), however, displayed no antibacterial activity against Gram-positive S. aureus ATCC 25923, the Gram-negative E. coli ATCC 25922 and a panel of clinical isolates of methicillin-resistant S. aureus (MRSA) strains, suggesting that 10 may act as a signal molecule for this strain. Although the same molecule has been synthesized previously, this is the first report to disclose the discovery of butrepyrazinone (10) from nature. Full article

Mangroves are woody plants located in tropical and subtropical intertidal coastal regions. The mangrove ecosystem is becoming a hot spot for natural product discovery and bioactivity survey. Diverse mangrove actinomycetes as promising and productive sources are worth being explored and uncovered. At the time of writing, we report 73 novel compounds and 49 known compounds isolated from mangrove actinomycetes including alkaloids, benzene derivatives, cyclopentenone derivatives, dilactones, macrolides, 2-pyranones and sesquiterpenes. Attractive structures such as salinosporamides, xiamycins and novel indolocarbazoles are highlighted. Many exciting compounds have been proven as potential new antibiotics, antitumor and antiviral agents, anti-fibrotic agents and antioxidants. Furthermore, some of their biosynthetic pathways have also been revealed. This review is an attempt to consolidate and summarize the past and the latest studies on mangrove actinomycetes natural product discovery and to draw attention to their immense potential as novel and bioactive compounds for marine drugs discovery. Full article