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1.
J Appl Microbiol ; 130(1): 196-207, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32654413

RESUMO

AIM: Research on prevention and cure of banana wilt is important to ensure the healthy development of the banana industry. In this study, antifungal mechanism of Streptomyces ma. FS-4 on fusarium wilt of banana was investigated. METHODS AND RESULTS: The physiological strain of banana fusarium pathogen Fusarium oxysporum f. sp. cubense Race 4 (FOC.4) was used as the target fungus, and the antifungal mechanism of the crude extract of Streptomyces ma. FS-4 was investigated. Eighteen different compounds identified by gas chromatography-mass spectrometry were composed of aldehydes, methyl, hydrocarbons, amides, esters and acids. FS-4 significantly inhibited the spore germination of the target fungi, with an EC50 of 22·78 µg ml-1 . After treatment with 100 µg ml-1 FS-4 crude extract, the N-acetylglucosamine content in the mycelium increased 1·95-fold. However, the extract had no significant effect on ß-1,3-glucanase. At the FS-4 crude extract dose of 100 µg ml-1 , the total sugar and protein contents decreased by 28·6 and 29·1% respectively, and the fat content was 41·3%. FS-4 significantly inhibited the activity of the mitochondrial complex III of Foc4, which was reduced by 52·45%. Moreover FS-4 reduced the activity of succinate dehydrogenase, a key enzyme in the Krebs cycle, by 60·2%. However, FS-4 had no significant effect on malate dehydrogenase. The membrane potential on the mitochondrial inner membrane was significantly reduced at the test concentration of 100 µg ml-1 . ROS gradually accumulated in the Foc4 hypha, and the burst was 3·97 times higher than the control. CONCLUSIONS: This study demonstrated that the antifungal mechanism of Streptomyces ma. FS-4 against Foc4 includes the destruction of the plasma membrane and mitochondrial dysfunction and finally induction of cell apoptosis. SIGNIFICANCE AND IMPACT OF THE STUDY: These results may indicate the prevention and control of banana wilt, which is of great significance to the healthy development of banana industry system.


Assuntos
Antifúngicos/farmacologia , Fusarium/efeitos dos fármacos , Musa/microbiologia , Doenças das Plantas/prevenção & controle , Streptomyces/química , Acetilglucosamina/metabolismo , Antifúngicos/química , Fusarium/crescimento & desenvolvimento , Fusarium/metabolismo , Hifas/efeitos dos fármacos , Hifas/crescimento & desenvolvimento , Hifas/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Doenças das Plantas/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Esporos Fúngicos/efeitos dos fármacos , Esporos Fúngicos/crescimento & desenvolvimento
2.
Chem Biol Interact ; 333: 109316, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33285127

RESUMO

Streptomyces hygroscopicus UFPEDA 3370 was fermented in submerged cultivation and the biomass extract was partitioned, obtaining a fraction purified named EB1. After purification of EB1 fraction, nigericin free acid was obtained and identified. Nigericin presented cytotoxic activity against several cancer cell lines, being most active against HL-60 (human leukemia) and HCT-116 (human colon carcinoma) cell lines, presenting IC50 and (IS) values: 0.0014 µM, (30.0) and 0.0138 µM (3.0), respectively. On HCT-116, nigericin caused apoptosis and autophagy. In this study, nigericin was also screened both in vitro and in silico against a panel of cancer-related kinases. Nigericin was able to inhibit both JAK3 and GSK-3ß kinases in vitro and its binding affinities were mapped through the intermolecular interactions with each target in silico.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Colorretais/patologia , Nigericina/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Domínio Catalítico , Linhagem Celular Tumoral , Humanos , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/química , Janus Quinase 3/metabolismo , Simulação de Acoplamento Molecular , Nigericina/química , Nigericina/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo
3.
J Med Chem ; 63(21): 12978-12991, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33100009

RESUMO

Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure-activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15 was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.


Assuntos
Carbazóis/química , Proteína Quinase C-delta/antagonistas & inibidores , Proteína Quinase C-theta/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Carbazóis/metabolismo , Carbazóis/farmacologia , Carbazóis/uso terapêutico , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-theta/metabolismo , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Água do Mar/microbiologia , Transdução de Sinais/efeitos dos fármacos , Streptomyces/química , Streptomyces/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de Xenoenxerto
4.
In Vivo ; 34(5): 3023-3026, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32871846

RESUMO

BACKGROUND/AIM: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One drug that has attracted interest is the antiparasitic compound ivermectin, a macrocyclic lactone derived from the bacterium Streptomyces avermitilis. We carried out a docking study to determine if ivermectin might be able to attach to the SARS-CoV-2 spike receptor-binding domain bound with ACE2. MATERIALS AND METHODS: We used the program AutoDock Vina Extended to perform the docking study. RESULTS: Ivermectin docked in the region of leucine 91 of the spike and histidine 378 of the ACE2 receptor. The binding energy of ivermectin to the spike-ACE2 complex was -18 kcal/mol and binding constant was 5.8 e-08. CONCLUSION: The ivermectin docking we identified may interfere with the attachment of the spike to the human cell membrane. Clinical trials now underway should determine whether ivermectin is an effective treatment for SARS-Cov2 infection.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/química , Peptidil Dipeptidase A/química , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/química , Betacoronavirus/patogenicidade , Sítios de Ligação/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos , Histidina/química , Humanos , Ivermectina/uso terapêutico , Leucina/química , Simulação de Acoplamento Molecular , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral/virologia , Streptomyces/química
5.
Proc Natl Acad Sci U S A ; 117(40): 24794-24801, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958639

RESUMO

The structure of lincomycin A consists of the unusual eight-carbon thiosugar core methyllincosamide (MTL) decorated with a pendent N-methylprolinyl moiety. Previous studies on MTL biosynthesis have suggested GDP-ᴅ-erythro-α-ᴅ-gluco-octose and GDP-ᴅ-α-ᴅ-lincosamide as key intermediates in the pathway. However, the enzyme-catalyzed reactions resulting in the conversion of GDP-ᴅ-erythro-α-ᴅ-gluco-octose to GDP-ᴅ-α-ᴅ-lincosamide have not yet been elucidated. Herein, a biosynthetic subpathway involving the activities of four enzymes-LmbM, LmbL, CcbZ, and CcbS (the LmbZ and LmbS equivalents in the closely related celesticetin pathway)-is reported. These enzymes catalyze the previously unknown biosynthetic steps including 6-epimerization, 6,8-dehydration, 4-epimerization, and 6-transamination that convert GDP-ᴅ-erythro-α-ᴅ-gluco-octose to GDP-ᴅ-α-ᴅ-lincosamide. Identification of these reactions completes the description of the entire lincomycin biosynthetic pathway. This work is significant since it not only resolves the missing link in octose core assembly of a thiosugar-containing natural product but also showcases the sophistication in catalytic logic of enzymes involved in carbohydrate transformations.


Assuntos
Lincomicina/biossíntese , Streptomyces/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Vias Biossintéticas , Lincomicina/química , Lincosamidas/química , Lincosamidas/metabolismo , Streptomyces/química , Streptomyces/enzimologia , Streptomyces/genética
6.
J Oleo Sci ; 69(10): 1273-1280, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-32908102

RESUMO

The study involved the isolation and identification of a member of Streptomyces griseorubens and the identification of its secondary metabolite content. Two extract samples were prepared by using butanol and chloroform. In the analyses of the extracts TLC, FT-IR, and GC-MS were employed. Butanol extract appeared to be dominated by three different pyrrole compounds (43.59%), while two fatty acids, linoleic- and erucic acids, were the most abundant secondary metabolites in the chloroform extract, 27.57% and 12.34%, respectively. Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro-compound was represented by a single and distinct band on the thin layer chromatography plate. In GC-MS spectra, it also constituted 13.50% of the butanol extract.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Ácido Linoleico/análise , Pirróis/análise , Streptomyces/química , Streptomyces/metabolismo , Butanóis , Cromatografia em Camada Delgada , Ácidos Erúcicos/análise , Cromatografia Gasosa-Espectrometria de Massas , Streptomyces/isolamento & purificação
7.
Appl Environ Microbiol ; 86(20)2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32801183

RESUMO

Inthomycins belong to a growing family of oxazole-containing polyketides and exhibit a broad spectrum of anti-oomycete and herbicidal activities. In this study, we purified inthomycins A and B from the metabolites of Streptomyces sp. strain SYP-A7193 and determined their chemical structures. Genome sequencing, comparative genomic analysis, and gene disruption of Streptomyces sp. SYP-A7193 showed that the inthomycin biosynthetic gene cluster (itm) belonged to the hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) system. Functional domain comparison and disruption/complementation experiments of itm12 resulted in the complete loss of inthomycins A and B and the subsequent restoration of their production, confirming that itm12 encodes a discrete acyltransferase (AT), and hence, itm was considered to belong to the trans-AT type I PKS system. Moreover, the disruption/complementation experiments of itm15 also resulted in the loss and restoration of inthomycin A and B formation. Further gene cloning, expression, purification, and activity verification of itm15 revealed that Itm15 is a cyclodehydratase that catalyzes a straight-chain dehydration reaction to form an oxazole ring for the biosynthesis of inthomycins A and B. Thus, we discovered a novel enzyme that catalyzes oxazole ring formation and elucidated the complete biosynthetic pathway of inthomycins.IMPORTANCE Streptomyces species produce numerous secondary metabolites with diverse structures and pharmacological activities that are beneficial for human health and have several applications in agriculture. In this study, hybrid nonribosomal peptide synthetase/polyketide synthase metabolites inthomycins A and B were isolated from after fermenting Streptomyces sp. SYP-A7193. Genome sequencing, gene disruption, gene complementation, heterologous expression, and activity assay revealed that the biosynthesis gene assembly line of inthomycins A and B was a 95.3-kb trans-AT type I PKS system in the strain SYP-A7193. More importantly, Itm15, a cyclodehydratase, was identified to be an oxazole ring formation enzyme required for the biosynthesis of inthomycins A and B; it is significant to discover this catalyzation reaction in the PKS/NRPS system in the field of microbiology. Our findings could provide further insights into the diversity of trans-AT type I PKS systems and the mechanism of oxazole cyclization involved in the biosynthesis of natural products.


Assuntos
Ácidos Graxos Insaturados/química , Genes Bacterianos , Família Multigênica , Oxazóis/metabolismo , Streptomyces/genética , Ácidos Graxos Insaturados/isolamento & purificação , Oxazóis/química , Oxazóis/isolamento & purificação , Streptomyces/química , Streptomyces/metabolismo
8.
J Med Microbiol ; 69(8): 1040-1048, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32692643

RESUMO

Given the increased reporting of multi-resistant bacteria and the shortage of newly approved medicines, researchers have been looking towards extreme and unusual environments as a new source of antibiotics. Streptomyces currently provides many of the world's clinical antibiotics, so it comes as no surprise that these bacteria have recently been isolated from traditional medicine. Given the wide array of traditional medicines, it is hoped that these discoveries can provide the much sought after core structure diversity that will be required of a new generation of antibiotics. This review discusses the contribution of Streptomyces to antibiotics and the potential of newly discovered species in traditional medicine. We also explore how knowledge of traditional medicines can aid current initiatives in sourcing new and chemically diverse antibiotics.


Assuntos
Antibacterianos/isolamento & purificação , Descoberta de Drogas/tendências , Microbiologia do Solo , Streptomyces/metabolismo , Animais , Antibacterianos/biossíntese , Cavernas/química , Invertebrados/química , Medicina Tradicional , Peptídeo Sintases/metabolismo , Plantas Medicinais/química , Policetídeo Sintases/metabolismo , Poríferos/química , Streptomyces/química , Streptomyces/enzimologia
9.
J Med Chem ; 63(15): 8432-8441, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32658465

RESUMO

The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy.


Assuntos
Proteínas de Bactérias/metabolismo , Enedi-Inos/metabolismo , Imunoconjugados/metabolismo , Metiltransferases/metabolismo , Streptomyces/metabolismo , Proteínas de Bactérias/química , Biocatálise , Vias Biossintéticas , Cristalografia por Raios X , Enedi-Inos/química , Imunoconjugados/química , Metiltransferases/química , Modelos Moleculares , Conformação Proteica , Streptomyces/química , Especificidade por Substrato
10.
Arch Microbiol ; 202(8): 2303-2309, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32556421

RESUMO

A novel Gram-stain positive, aerobic, non-motile actinobacterium, designated strain YC537T, was isolated from lake sediment collected from Yenicaga Lake, Bolu, Turkey, and subjected to a polyphasic taxonomic approach. The organism had phylogenetic, chemotaxonomic, cultural and morphological properties consistent with its classification in the genus Streptomyces. 16S rRNA gene sequence analysis of strain YC537T showed that it is closely related to the type strain of Streptomyces ziwulingensis F22T (97.9% sequence similarity), Streptomyces tauricus JCM 4837 T (97.7%) and Streptomyces beijiangensis NBRC 100044 T (97.6%). The cell wall of the strain contained LL-diaminopimelic acid and the cell-wall sugars were glucose, galactose and ribose. The major phospholipids of strain YC537T were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. The predominant menaquinones were identified as MK-9(H6) and MK-9(H8). The major cellular fatty acids were iso-C16:0, iso-C14:0, anteiso-C15:0 and iso-C15:0. Consequently, strain YC537T is considered to represent a novel species in the genus Streptomyces, for which the name Streptomyces boluensis sp. nov. is proposed. The type strain is YC537T (= KCTC 39750 T = DSM 102303 T).


Assuntos
Sedimentos Geológicos/microbiologia , Lagos/microbiologia , Filogenia , Streptomyces/classificação , Ácido Diaminopimélico/análise , Ácidos Graxos/análise , Fosfolipídeos/análise , RNA Ribossômico 16S/genética , Especificidade da Espécie , Streptomyces/química , Streptomyces/genética , Streptomyces/isolamento & purificação , Vitamina K 2/análise
11.
Food Chem ; 330: 127225, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32569931

RESUMO

The whole genome of Streptomyces violascens (=ATCC 27968) was sequenced and the cloning and expression of OUC-Lipase 6 were conducted in Bacillus subtilis WB800. The recombinant enzyme belongs to the lipolytic enzymes family V. OUC-Lipase 6 showed optimal activity at 30 °C and pH 9.0, and retained 90.2% of its activity in an alkaline buffer (pH 8.0, 30 °C and 96 h). OUC-Lipase 6 showed good stability under medium temperature conditions (residual activity of 68.8%, pH 8.0, 45 °C and 96 h). OUC-Lipase 6 could selectively hydrolyze fatty acids on the glyceride backbone, thus improving the contents of DHA and EPA in codfish oil. OUC-Lipase 6 also showed regioselectivity, resulting in a better enrichment efficiency for EPA than DHA. After hydrolyzing for 36 h via OUC-Lipase 6, the contents of EPA and DHA were improved to 3.24-fold and 1.98-fold, respectively.


Assuntos
Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Lipase/metabolismo , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/química , Genoma Bacteriano , Glicerídeos/química , Hidrólise , Streptomyces/química , Streptomyces/genética , Streptomyces/metabolismo , Especificidade por Substrato
12.
Sci Rep ; 10(1): 10092, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572099

RESUMO

A Kashmir Himalayan (India) soil isolate, Streptomyces sp. SM01 was subjected to small scale fermentation for the production of novel antimicrobials, picolinamycin (SM1). The production has been optimized which found to be maximum while incubated in AIA medium (pH 7) for 7 days at 30 °C. Seven days grew crude cell-free culture media (50 µL) showed a larger zone of inhibition against Staphylococcus aureus compared to streptomycin (5 µg) and ampicillin (5 µg). Extraction, purification, and chemical analysis of the antimicrobial component has been proved to be a new class of antibiotic with 1013 dalton molecular weight. We have named this new antibiotic as picolinamycin for consisting picolinamide moiety in the center of the molecule and produced by a Streptomyces sp. In general, the antimicrobial potency of this newly characterized antibiotic found to be higher against Gram-positive organisms than the tested Gram-negative organisms. The MIC of this antimicrobial compound was found to be 0.01 µg/ml for tested Gram-positive organisms and 0.02 to 5.12 µg/ml for Gram-negative organisms. Furthermore, it showed strong growth impairments of several multidrug resistance (MDR) strains, including methicillin-resistant strains of Staphylococci and Enterococci with the MIC value of 0.04 to 5.12 µg/ml and MDR (but methicillin-sensitive) strains of S. aureus with the MIC value of 0.084 µg/ml. It also showed anti-mycobacterial potential in higher concentrations (MIC is 10.24 µg/ml). Picolinamycin however did not show toxicity against tested A549 human cell line indicating that the spectrum of its activity limited within bacteria only.


Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Streptomyces/metabolismo , Estreptomicina/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Índia , Testes de Sensibilidade Microbiana , Solo/química , Microbiologia do Solo , Staphylococcus/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Streptomyces/química
13.
Arch Microbiol ; 202(9): 2401-2409, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32591909

RESUMO

In this study, the structure of the purified extracellular eumelanin pigment isolated from Streptomyces spp. was elucidated by detailed analysis via two different spectroscopic techniques (FT-IR and NMR). In vitro antiproliferative effects of eumelanin were evaluated on HeLa cell line. These experiments were carried out with the evaluation of the parameters including cell viability, cell index, and mitotic index. With the cell viability and cell index, IC50 concentration of eumelanin was determined as 10 µM. This result showed that the IC50 concentration of eumelanin decreased the values of cell viability, cell index and mitotic index. These changes are statistically significant (p < 0.01). The ability of the dissolved eumelanin (250 µg mL-1) to scavenge free radicals was determined via DPPH and ABTS and was shown to be about 87.73% and 75.2%, respectively, compared with standard antioxidants. It was observed that dry weights of eumelanin yield among the selected strains ranged from 160 to 240 mg L-1. The strain with the highest production potential was selected for 16S rDNA sequence analysis and, accordingly, the selected strain BSB49 was identified as Streptomyces parvus and the sequence analysis results were deposited in NCBI under accession number MK894155.


Assuntos
Sobrevivência Celular/efeitos dos fármacos , Melaninas/química , Melaninas/farmacologia , Streptomyces/química , Células HeLa , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , RNA Ribossômico 16S/genética , Espectroscopia de Infravermelho com Transformada de Fourier , Streptomyces/genética
14.
Arch Microbiol ; 202(8): 2083-2092, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32494868

RESUMO

Chloramphenicol (CAP) and cyclo-(L-Val-L-Pro) were previously isolated from Streptomyces sp., SUK 25 which exhibited a high potency against methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to profile gene expression of MRSA treated with CAP and cyclo-(L-Val-L-Pro) compounds using DNA microarray. Treatment of MRSA with CAP resulted in upregulation of genes involved in protein synthesis, suggesting the coping mechanism of MRSA due to the inhibition of protein synthesis effect from CAP. Most upregulated genes in cyclo-(L-Val-L-Pro) were putative genes with unknown functions. Interestingly, genes encoding ribosomal proteins, cell membrane synthesis, DNA metabolism, citric acid cycle and virulence were downregulated in MRSA treated with cyclo-(L-Val-L-Pro) compound, suggesting the efficacy of this compound in targeting multiple biological pathways. Contrary to CAP, with only a single target, cyclo-(L-Val-L-Pro) isolated from this study had multiple antimicrobial targets that can delay antibiotic resistance and hence is a potential antimicrobial agent of MRSA.


Assuntos
Cloranfenicol/farmacologia , Regulação para Baixo/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Perfilação da Expressão Gênica , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Streptomyces/química
15.
J Antibiot (Tokyo) ; 73(8): 534-541, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32393809

RESUMO

Iseolides A-C (1-3), three new glycosylated macrolides, were identified from the culture extract of Streptomyces sp. DC4-5 isolated from a stony coral Dendrophyllia. Extensive analysis of one- and two-dimensional NMR data, coupled with MS/MS analytical data, revealed that iseolides are new congeners of 36-membered macrolides, PM100117 and PM100118, previously reported from a marine-derived Streptomyces. Iseolides showed potent antifungal activity against a plant pathogen Glomerella cingulata and human pathogens Candida albicans and Trichophyton rubrum with MIC in the range of 0.19-6.25 µg/mL.


Assuntos
Actinobacteria/química , Antozoários/química , Antifúngicos/química , Macrolídeos/química , Streptomyces/química , Animais , Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Colletotrichum/efeitos dos fármacos , Humanos , Macrolídeos/farmacologia , Imagem por Ressonância Magnética/métodos , Camundongos , Testes de Sensibilidade Microbiana/métodos , Espectrometria de Massas em Tandem/métodos
16.
J Antibiot (Tokyo) ; 73(8): 548-553, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404990

RESUMO

A new cytotoxic agent designated as 2-epi-anthracimycin (1) was isolated along with anthracimycin and anthracimycin B (2-demethylanthracimycin) from the culture broth of the marine-derived actinomycete Streptomyces sp. OPMA00631. The structure of 1 was elucidated based on spectroscopic analyses (1D and 2D NMR data and ROESY correlations). Compound 1 exhibited cytotoxicity against Jurkat cells with an IC50 value of 50.5 µM in 20 h. The effect of 1 on the cell cycle distribution of Jurkat cells was investigated. Compound 1 (7.80 µM) increased G1 phase cells from 51.1 to 62.0% and conversely, decreased G2 and M phase cells from 30.7 to 19.3 % in 20 h. At a higher concentration, 1 (250 µM) markedly increased subG1 phase cells (1.9% at 0 h to 16.5% at 20 h), while the proportion of G1 phase cells was maintained (62.3%). These results suggest that 1 exhibits cytotoxicity against Jurkat cells by arresting the cell cycle at the G1 phase.


Assuntos
Actinobacteria/química , Organismos Aquáticos/química , Citotoxinas/química , Citotoxinas/farmacologia , Policetídeos/química , Policetídeos/farmacologia , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Células Jurkat
17.
J Biol Chem ; 295(28): 9752-9765, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32303639

RESUMO

The bacterial protein WhiD belongs to the Wbl family of iron-sulfur [Fe-S] proteins present only in the actinomycetes. In Streptomyces coelicolor, it is required for the late stages of sporulation, but precisely how it functions is unknown. Here, we report results from in vitro and in vivo experiments with WhiD from Streptomyces venezuelae (SvWhiD), which differs from S. coelicolor WhiD (ScWhiD) only at the C terminus. We observed that, like ScWhiD and other Wbl proteins, SvWhiD binds a [4Fe-4S] cluster that is moderately sensitive to O2 and highly sensitive to nitric oxide (NO). However, although all previous studies have reported that Wbl proteins are monomers, we found that SvWhiD exists in a monomer-dimer equilibrium associated with its unusual C-terminal extension. Several Wbl proteins of Mycobacterium tuberculosis are known to interact with its principal sigma factor SigA. Using bacterial two-hybrid, gel filtration, and MS analyses, we demonstrate that SvWhiD interacts with domain 4 of the principal sigma factor of Streptomyces, σHrdB (σHrdB 4). Using MS, we determined the dissociation constant (Kd ) for the SvWhiD-σHrdB 4 complex as ∼0.7 µm, consistent with a relatively tight binding interaction. We found that complex formation was cluster dependent and that a reaction with NO, which was complete at 8-10 NO molecules per cluster, resulted in dissociation into the separate proteins. The SvWhiD [4Fe-4S] cluster was significantly less sensitive to reaction with O2 and NO when SvWhiD was bound to σHrdB 4, consistent with protection of the cluster in the complex.


Assuntos
Proteínas de Bactérias , Proteínas de Ligação a DNA , Fator sigma , Streptomyces , Fatores de Transcrição , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Mycobacterium tuberculosis/química , Mycobacterium tuberculosis/metabolismo , Fator sigma/química , Fator sigma/metabolismo , Streptomyces/química , Streptomyces/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
18.
Biomed Res Int ; 2020: 6402607, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32258133

RESUMO

The mangrove ecosystem of Malaysia remains yet to be fully explored for potential microbes that produce biologically active metabolites. In the present study, a mangrove-derived Streptomyces sp. strain MUSC 14 previously isolated from the state of Pahang, Malaysia Peninsula, was studied for its potential in producing antioxidant metabolites. The identity of Streptomyces sp. strain MUSC14 was consistent with the genotypic and phenotypic characteristics of the Streptomyces genus. The antioxidant potential of Streptomyces sp. strain MUSC 14 was determined through screening of its methanolic extract against sets of antioxidant assays. The results were indicative of Streptomyces sp. strain MUSC 14 displaying strong antioxidant activity against ABTS, DPPH free radicals and metal chelating activity of 62.71 ± 3.30%, 24.71 ± 2.22%, and 55.82 ± 2.35%, respectively. The result of ferric reducing activity measured in terms of dose was equivalent to 2.35-2.45 µg of positive control ascorbic acid. Furthermore, there was a high correlation between the total phenolic content and the antioxidant activities with r = 0.979, r = 0.858, and r = 0.983 representing ABTS, DPPH, and metal chelation, respectively. Overall, the present study suggests that Streptomyces sp. strain MUSC 14 from mangrove forest soil has potential to produce antioxidant metabolites that can be further exploited for therapeutic application.


Assuntos
Antioxidantes/análise , Microbiologia do Solo , Streptomyces , Áreas Alagadas , Malásia , Streptomyces/química , Streptomyces/isolamento & purificação
19.
J Antibiot (Tokyo) ; 73(8): 542-547, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32332871

RESUMO

Two new chlorinated bis-indole alkaloids, dionemycin (1) and 6-OMe-7',7″-dichorochromopyrrolic acid (2), along with seven known analogs 3-9, were isolated from the deep-sea derived Streptomyces sp. SCSIO 11791. Their structures were elucidated by extensive HRESIMS, and 1D and 2D NMR data analysis. In vitro antibacterial and cytotoxic assays revealed that, compound 1, shows anti-staphylococcal activity with an MIC range of 1-2 µg/mL against six clinic strains of methicillin-resistant Staphylococcus aureus (MRSA) isolated from human and pig. Additionally, compound 1 displayed cytotoxic activity against human cancer cell lines NCI-H460, MDA-MB-231, HCT-116, HepG2, and noncancerous MCF10A with an IC50 range of 3.1-11.2 µM. Analysis of the structure-activity relationship reveals that the chlorine atom at C-6″ could be pivotal for conferring their bioactivities, thus providing hints on chemical modifications on bis-indole alkaloid scaffold in drug design.


Assuntos
Organismos Aquáticos/química , Citotoxinas/química , Citotoxinas/farmacologia , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Streptomyces/química , Animais , Linhagem Celular , Linhagem Celular Tumoral , Células HCT116 , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Suínos
20.
Proc Natl Acad Sci U S A ; 117(15): 8449-8454, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32217738

RESUMO

Type I polyketide synthases (T1PKSs) are one of the most extensively studied PKSs, which can act either iteratively or via an assembly-line mechanism. Domains in the T1PKSs can readily be predicted by computational tools based on their highly conserved sequences. However, to distinguish between iterative and noniterative at the module level remains an overwhelming challenge, which may account for the seemingly biased distribution of T1PKSs in fungi and bacteria: small iterative monomodular T1PKSs that are responsible for the enormously diverse fungal natural products exist almost exclusively in fungi. Here we report the discovery of iterative T1PKSs that are unexpectedly both abundant and widespread in Streptomyces Seven of 11 systematically selected T1PKS monomodules from monomodular T1PKS biosynthetic gene clusters (BGCs) were experimentally confirmed to be iteratively acting, synthesizing diverse branched/nonbranched linear intermediates, and two of them produced bioactive allenic polyketides and citreodiols as end products, respectively. This study indicates the huge potential of iterative T1PKS BGCs from streptomycetes in the discovery of novel polyketides.


Assuntos
Proteínas de Bactérias/metabolismo , Policetídeo Sintases/metabolismo , Streptomyces/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Família Multigênica , Policetídeo Sintases/química , Policetídeo Sintases/genética , Domínios Proteicos , Streptomyces/química , Streptomyces/genética
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