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Fulltext Targeted Isolation of Anti-Trypanosomal Naphthofuran-Quinone Compounds from the Mangrove Plant Avicennia lanata

Mazlan NW, Clements C, Edrada-Ebel R

Mar Drugs, 2020 Dec 21;18(12).
PMID: 33371387 DOI: 10.3390/md18120661

The discovery of new secondary metabolites from natural origins has become more challenging in natural products research. Different approaches have been applied to target the isolation of new bioactive metabolites from plant extracts. In this study, bioactive natural products were isolated from the crude organic extract of the mangrove plant Avicennia lanata collected from the east coast of Peninsular Malaysia in the Setiu Wetlands, Terengganu, using HRESI-LCMS-based metabolomics-guided isolation and fractionation. Isolation work on the crude extract A. lanata used high-throughput chromatographic techniques to give two new naphthofuranquinone derivatives, hydroxyavicenol C (1) and glycosemiquinone (2), along with the known compounds avicenol C (3), avicequinone C (4), glycoquinone (5), taraxerone (6), taraxerol (7), β-sitosterol (8) and stigmasterol (9). The elucidation and identification of the targeted bioactive compounds used 1D and 2D-NMR and mass spectrometry. Except for 6-9, all isolated naphthoquinone compounds (1-5) from the mangrove plant A. lanata showed significant anti-trypanosomal activity on Trypanosoma brucei brucei with MIC values of 3.12-12.5 μM. Preliminary cytotoxicity screening against normal prostate cells (PNT2A) was also performed. All compounds exhibited low cytotoxicity, with compounds 3 and 4 showing moderate cytotoxicity of 78.3% and 68.6% of the control values at 100 μg/mL, respectively.
Metabolomic Profiling of Malaysian and New Zealand Honey Using Concatenated NMR and HRMS Datasets

Yusoff YM, Abbott G, Young L, Edrada-Ebel R

Metabolites, 2022 Jan 17;12(1).
PMID: 35050207 DOI: 10.3390/metabo12010085

This study aims to compare the metabolomic profiles of Malaysian and New Zealand honey while determining their anti-oncogenic activity for potential prophylactic functions. Metabolomics tools including multivariate analysis were applied on concatenated LC-HRMS and NMR datasets to afford an intensive chemical profile of honey samples and have a snapshot of the bioactive metabolites in the respective collections. Malaysian samples were found to have higher sugar and polyphenolic content, while New Zealand samples afforded higher concentration of low molecular weight (MW) lipids. However, New Zealand honey collected from the northern islands had higher concentration of acetylated saccharides, while those from the southern islands yielded higher low MW phenolic metabolites that were comparable to Malaysian honey. Mild anti-oncogenic compounds against breast cancer cell line ZR75 were putatively identified in Malaysian honey that included earlier described antioxidants such as gingerdiol, 2-hexylphenol-O-β-D-xylopyranoside, plastoquinone, tropine isovalerate, plumerinine, and 3,5-(12-phenyl-8-dodecenyl)resorcinol, along with several phenolic esters and lignans.
Fulltext Isolation and characterization of cyclo-(tryptophanyl-prolyl) and chloramphenicol from Streptomyces sp. SUK 25 with antimethicillin-resistant Staphylococcus aureus activity

Alshaibani MM, Jalil J, Sidik NM, Edrada-Ebel R, Zin NM

Drug Des Devel Ther, 2016;10:1817-27.
PMID: 27330275 DOI: 10.2147/DDDT.S101212

BACKGROUND: Zingiber spectabile, commonly known as Beehive Ginger, is used as an ethnobotanical plant in many countries as an appetizer or to treat stomachache, toothache, muscle sprain, and as a cure for swelling, sores and cuts. This is the first report of isolation of Streptomyces strain from the root of this plant. Strain Universiti Kebangsaan 25 (SUK 25) has a very high activity to produce secondary metabolites against methicillin-resistant Staphylococcus aureus (MRSA), which is associated with high morbidity and mortality rates due to acquired multidrug resistance genes and causes medication failure in some clinical cases worldwide. Phylogenetic analysis based on the 16S ribosomal RNA gene sequence exhibited that the most closely related strain was Streptomyces omiyaensis NBRC 13449T (99.0% similarity).
AIM: This study was conducted to carry out the extraction, identification, and biological evaluation of active metabolites isolated from SUK 25 against three MRSA strains, namely, MRSA ATCC 43300, MRSA ATCC 33591, and MRSA ATCC 49476.
MATERIALS AND METHODS: The production of secondary metabolites by this strain was optimized through Thronton's media. Isolation, purification, and identification of the bioactive compounds were carried out using reversed-phase high-performance liquid chromatography, high-resolution mass spectrometry, Fourier transform infrared, and one-dimensional and two-dimensional nuclear magnetic resonance.
RESULTS: During screening procedure, SUK 25 exhibited good antimicrobial potential against several strains of MRSA. The best biological activity was shown from fraction number VII and its subfractions F2 and F3 with minimum inhibitory concentration values at 16 µg/mL and 8 µg/mL, respectively. These two subfractions were identified as diketopiperazine cyclo-(tryptophanyl-prolyl) and chloramphenicol.
CONCLUSION: On the basis of obtained results, SUK 25 isolated from Z. spectabile can be regarded as a new valuable source to produce secondary metabolites against bacteria, especially MRSA.
Streptomyces kebangsaanensis sp. nov., an endophytic actinomycete isolated from an ethnomedicinal plant, which produces phenazine-1-carboxylic acid

Sarmin NIM, Tan GYA, Franco CMM, Edrada-Ebel R, Latip J, Zin NM

Int J Syst Evol Microbiol, 2013 Oct;63(Pt 10):3733-3738.
PMID: 23645019 DOI: 10.1099/ijs.0.047878-0

A spore-forming streptomycete designated strain SUK12(T) was isolated from a Malaysian ethnomedicinal plant. Its taxonomic position, established using a polyphasic approach, indicates that it is a novel species of the genus Streptomyces. Morphological and chemical characteristics of the strain were consistent with those of members of the genus Streptomyces. Analysis of the almost complete 16S rRNA gene sequence placed strain SUK12(T) in the genus Streptomyces where it formed a distinct phyletic line with recognized species of this genus. The strain exhibited highest sequence similarity to Streptomyces corchorusii DSM 40340(T) (98.2 %) followed by Streptomyces chrestomyceticus NRRL B-3310(T) (98.1 %). The G+C content of the genomic DNA was 74 mol%. Chemotaxonomic data [MK-9(H8) as the major menaquinone; LL-diaminopimelic acid as a component of cell-wall peptidoglycan; C12 : 0, C14 : 0, C15 : 0 and C17 : 1 as the major fatty acids; phospholipid type II] supported the affiliation of strain SUK12(T) to the genus Streptomyces. The results of the phylogenetic analysis and phenotypic data derived from this and previous studies allowed the genotypic and phenotypic differentiation of strain SUK12(T) from the related species of the genus Streptomyces. The DNA-DNA relatedness value between strain SUK12(T) and S. corchorusii DSM 40340(T) is 18.85±4.55 %. Strain SUK12(T) produces phenazine-1-carboxylic acid, known as tubermycin B, an antibacterial agent. It is proposed, therefore, that strain SUK12(T) ( = DSM 42048(T) = NRRL B-24860(T)) be classified in the genus Streptomyces as the type strain of Streptomyces kebangsaanensis sp. nov.
Fulltext Biodiscovery of Potential Antibacterial Diagnostic Metabolites from the Endolichenic Fungus Xylaria venustula Using LC-MS-Based Metabolomics

Santiago KAA, Edrada-Ebel R, Dela Cruz TEE, Cheow YL, Ting ASY

Biology (Basel), 2021 Mar 04;10(3).
PMID: 33806264 DOI: 10.3390/biology10030191

Three species of the lichen Usnea (U. baileyi (Stirt.) Zahlbr., U. bismolliuscula Zahlbr. and U. pectinata Stirt.) and nine associated endolichenic fungi (ELF) were evaluated using a metabolomics approach. All investigated lichen crude extracts afforded antibacterial activity against Staphylococcus aureus (minimum inhibitory concentration (MIC): 0.0625 mg/mL), but none was observed against Escherichia coli, while the ELF extract Xylaria venustula was found to be the most active against S. aureus (MIC: 2.5 mg/mL) and E. coli (MIC: 5 mg/mL). X. venustula was fractionated and tested for to determine its antibacterial activity. Fractions XvFr1 to 5 displayed bioactivities against both test bacteria. Selected crude extracts and fractions were subjected to metabolomics analyses using high-resolution LC-MS. Multivariate analyses showed the presence of five secondary metabolites unique to bioactive fractions XvFr1 to 3, which were identified as responsible for the antibacterial activity of X. venustula. The p-values of these metabolites were at the margin of significance level, with methyl xylariate C (P_60) being the most significant. However, their high variable importance of projection (VIP) scores (>5) suggest these metabolites are potential diagnostic metabolites for X. venustula for "dual" bioactivity against S. aureus and E. coli. The statistical models also showed the distinctiveness of metabolites produced by lichens and ELF, thus supporting our hypotheses of ELF functionality similar to plant endophytes.
Fulltext Isolation, Purification, and Characterization of Five Active Diketopiperazine Derivatives from Endophytic Streptomyces SUK 25 with Antimicrobial and Cytotoxic Activities

Alshaibani M, Zin NM, Jalil J, Sidik N, Ahmad SJ, Kamal N, et al.

J Microbiol Biotechnol, 2017 07 28;27(7):1249-1256.
PMID: 28535606 DOI: 10.4014/jmb.1608.08032

In our search for new sources of bioactive secondary metabolites from Streptomyces sp., the ethyl acetate extracts from endophytic Streptomyces SUK 25 afforded five active diketopiperazine (DKP) compounds. The aim of this study was to characterize the bioactive compounds isolated from endophytic Streptomyces SUK 25 and evaluate their bioactivity against multiple drug resistance (MDR) bacteria such as Enterococcus raffinosus, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter spp., and their cytotoxic activities against the human hepatoma (HepaRG) cell line. The production of secondary metabolites by this strain was optimized through Thornton's medium. Isolation, purification, and identification of the bioactive compounds were carried out using high-performance liquid chromatography, high-resolution mass liquid chromatography-mass spectrometry, Fourier transform infrared spectroscopy, and nuclear magnetic resonance, and cryopreserved HepaRG cells were selected to test the cytotoxicity. The results showed that endophytic Streptomyces SUK 25 produces four active DKP compounds and an acetamide derivative, which were elucidated as cyclo-(L-Val-L-Pro), cyclo-(L-Leu-L-Pro), cyclo-(L-Phe-L-Pro), cyclo-(L-Val-L-Phe), and N-(7-hydroxy-6-methyl-octyl)-acetamide. These active compounds exhibited activity against methicillin-resistant S. aureus ATCC 43300 and Enterococcus raffinosus, with low toxicity against human hepatoma HepaRG cells. Endophytic Streptomyces SUK 25 has the ability to produce DKP derivatives biologically active against some MDR bacteria with relatively low toxicity against HepaRG cells line.
Metabolomics-Guided Isolation of Anti-Trypanosomal Compounds from Endophytic Fungi of the Mangrove plant Avicennia Lanata

Mazlan NW, Tate R, Yusoff YM, Clements C, Edrada-Ebel R

Curr Med Chem, 2020;27(11):1815-1835.
PMID: 31272343 DOI: 10.2174/0929867326666190704130105

Endophytic fungi have been explored not just for their ecological functions but also for their secondary metabolites as a new source of these pharmacologically active natural products. Accordingly, many structurally unique and biologically active compounds have been obtained from the cultures of endophytic fungi. Fusarium sp. and Lasiodiplodia theobromae were isolated from the root and stem of the mangrove plant Avicennia lanata, respectively, collected from Terengganu, Malaysia. High-resolution mass spectrometry and NMR spectroscopy were used as metabolomics profiling tools to identify and optimize the production of bioactive secondary metabolites in both strains at different growth stages and culture media. The spectral data was processed by utilizing Mzmine 2, a quantitative expression analysis software and an in house MS-Excel macro coupled with the Dictionary of Natural Products databases for dereplication studies. The investigation for the potential bioactive metabolites from a 15-day rice culture of Fusarium sp. yielded four 1,4- naphthoquinone with naphthazarin structures (1-4). On the other hand, the endophytic fungus L. theobromae grown on the 15-day solid rice culture produced dihydroisocoumarins (5-8). All the isolated compounds (1-8) showed significant activity against Trypanosoma brucei brucei with MIC values of 0.32-12.5 µM. Preliminary cytotoxicity screening against normal prostate cells (PNT2A) was also performed. All compounds exhibited low cytotoxicity, with compounds 3 and 4 showing the lowest cytotoxicity of only 22.3% and 38.6% of the control values at 100 µg/mL, respectively. Structure elucidation of the isolated secondary metabolites was achieved using 2D-NMR and HRESI-MS as well as comparison with literature data.
Fulltext Erratum to: Isolation, Purification, and Characterization of Five Active Diketopiperazine Derivatives from Endophytic Streptomyces SUK 25 with Antimicrobial and Cytotoxic Activities

Alshaibani MM, Mohamad Zin N, Jalil J, Sidik NM, Ahmad SJ, Kamal N, et al.

J Microbiol Biotechnol, 2017 11 28;27(11):2074.
PMID: 29169008 DOI: 10.4014/jmb.2017.2711.2074

This erratum is being published to correct the 2nd author's name of above manuscript by Alshaibani et al. that was published in Journal of Microbiology and Biotechnology (2017, 27: 1249-1256). The 2nd author name(Noraziah MohamadZin) should appear as 'Noraziah Mohamad Zin'.
Fulltext Gancidin W, a potential low-toxicity antimalarial agent isolated from an endophytic Streptomyces SUK10

Zin NM, Baba MS, Zainal-Abidin AH, Latip J, Mazlan NW, Edrada-Ebel R

Drug Des Devel Ther, 2017;11:351-363.
PMID: 28223778 DOI: 10.2147/DDDT.S121283

Endophytic Streptomyces strains are potential sources for novel bioactive molecules. In this study, the diketopiperazine gancidin W (GW) was isolated from the endophytic actinobacterial genus Streptomyces, SUK10, obtained from the bark of Shorea ovalis tree, and it was tested in vivo against Plasmodium berghei PZZ1/100. GW exhibited an inhibition rate of nearly 80% at 6.25 and 3.125 μg kg-1 body weight on day four using the 4-day suppression test method on male ICR strain mice. Comparing GW at both concentrations with quinine hydrochloride and normal saline as positive and negative controls, respectively, 50% of the mice treated with 3.125 μg kg-1 body weight managed to survive for more than 11 months after infection, which almost reached the life span of normal mice. Biochemical tests of selected enzymes and proteins in blood samples of mice treated with GW were also within normal levels; in addition, no abnormalities or injuries were found on internal vital organs. These findings indicated that this isolated bioactive compound from Streptomyces SUK10 exhibits very low toxicity and is a good candidate for potential use as an antimalarial agent in an animal model.
In vivo antimalarial activity of the endophytic actinobacteria, Streptomyces SUK 10

Baba MS, Zin NM, Hassan ZA, Latip J, Pethick F, Hunter IS, et al.

J Microbiol, 2015 Dec;53(12):847-55.
PMID: 26626355 DOI: 10.1007/s12275-015-5076-6

Endophytic bacteria, such as Streptomyces, have the potential to act as a source for novel bioactive molecules with medicinal properties. The present study was aimed at assessing the antimalarial activity of crude extract isolated from various strains of actinobacteria living endophytically in some Malaysian medicinal plants. Using the four day suppression test method on male ICR strain mice, compounds produced from three strains of Streptomyces (SUK8, SUK10, and SUK27) were tested in vivo against Plasmodium berghei PZZ1/100 in an antimalarial screen using crude extracts at four different concentrations. One of these extracts, isolated from Streptomyces SUK10 obtained from the bark of Shorea ovalis tree, showed inhibition of the test organism and was further tested against P. berghei-infected mice for antimalarial activity at different concentrations. There was a positive relationship between the survival of the infected mouse group treated with 50 µg/kg body weight (bw) of ethyl acetate-SUK10 crude extract and the ability to inhibit the parasites growth. The parasite inhibition percentage for this group showed that 50% of the mice survived for more than 90 days after infection with the parasite. The nucleotide sequence and phylogenetic tree suggested that Streptomyces SUK10 may constitute a new species within the Streptomyces genus. As part of the drug discovery process, these promising finding may contribute to the medicinal and pharmaceutical field for malarial treatment.

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