RESUMEN
Pactamycin (PCT), an antibiotic produced by Streptomyces pactum, is a five-membered ring aminocyclitol that is active against a variety of Gram-positive and Gram-negative microorganisms, as well as several animal tumor lines in culture and in vivo. Pactamycin targets the small ribosomal subunit and inhibits protein synthesis in bacteria, archaea, and eukaryotes, but due to its toxicity is used only as a tool for biochemical research. Prompted by the successful and well-established procedure for the derivatization of antibiotics, we modified pactamycin by tethering basic amino acids to the free primary amino group of the aminocyclitol ring. Specifically, lysine, ornithine, and histidine were conjugated via an amide bond, and the antimicrobial activity of the derivatives was evaluated both in vivo and in vitro. According to our results, their antimicrobial activity was maintained at almost equal levels, while their toxicity was reduced compared to the parent molecule. These findings suggest that the new pactamycin derivatives can be considered as promising pharmacophores for the development of new antimicrobials that are able to combat the dangerously increasing resistance of pathogens to antibiotics.
Asunto(s)
Pruebas de Sensibilidad Microbiana , Pactamicina , Pactamicina/farmacología , Pactamicina/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Animales , Streptomyces/química , Antiinfecciosos/farmacología , Antiinfecciosos/química , Antiinfecciosos/síntesis química , Ratones , Humanos , Relación Estructura-ActividadRESUMEN
Eighteen nitrogen-containing compounds (1-18) were isolated from cultures of the lichen-associated Streptomyces flavidovirens collected from the Qinghai-Tibet Plateau, including seven phenazine derivatives with three new ones, named subphenazines A-C (2-4), two new furan pyrrolidones (8-9), and nine known alkaloids. The structures were elucidated by spectroscopic data analysis, and absolute configurations were determined by single-crystal X-ray diffraction and ECD calculations. The phenazine-type derivatives, in particular compound 3, exhibited significantly better antineuroinflammatory activity than other isolated compounds (8-18). Compound 3 inhibited the release of proinflammatory cytokines including IL-6, TNF-α, and PGE2, and the nuclear translocation of NF-κB; it also reduced the oxidative stress and activated the Nrf2 signaling pathway in LPS-induced BV2 microglia cells. In vivo anti-inflammatory activity in zebrafish indicated that 3 inhibited LPS-stimulated ROS generation. These findings suggested that compound 3 might be a potent antineuroinflammatory agent through the regulation of the NF-κB/Nrf2 signaling pathways.
Asunto(s)
Antiinflamatorios , Líquenes , FN-kappa B , Fenazinas , Streptomyces , Pez Cebra , Animales , Streptomyces/química , Líquenes/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Fenazinas/farmacología , Fenazinas/química , Estructura Molecular , FN-kappa B/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Microglía/efectos de los fármacos , Lipopolisacáridos/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Six new angucycline structures, including spirocyclione A (1), which contains an unusual oxaspiro[5.5]undecane architecture, and its ring-A-cleaved product spirocyclione B (2), were discovered by heterologous expression of a type II polyketide biosynthetic gene cluster captured from a marine actinomycete strain Streptomyces sp. HDN155000. Three flavoprotein monooxygenases are confirmed to be responsible for the oxidative carbon skeleton rearrangements in the biosynthesis of compounds 1 and 2. The obtained compounds showed promising cytotoxicity against different types of cancer cells.
Asunto(s)
Oxigenasas de Función Mixta , Streptomyces , Streptomyces/enzimología , Streptomyces/química , Streptomyces/metabolismo , Oxigenasas de Función Mixta/metabolismo , Estructura Molecular , Familia de Multigenes , Flavoproteínas/metabolismo , Flavoproteínas/química , Humanos , Ensayos de Selección de Medicamentos Antitumorales , Catálisis , Compuestos de Espiro/química , Compuestos de Espiro/metabolismo , Policétidos/química , Policétidos/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Antraquinonas/química , Antraquinonas/metabolismo , Anguciciclinas y AnguciclinonasRESUMEN
A talented endophytic Streptomyces sp. PH9030 is derived from the medicinal plant Kadsura coccinea (Lem.) A.C. Smith. The undescribed naphthoquinone naphthgeranine G (5) and seven previously identified compounds, 6-12, were obtained from Streptomyces sp. PH9030. The structure of 5 was identified by comprehensive examination of its HRESIMS, 1D NMR, 2D NMR and ECD data. The inhibitory activities of all the compounds toward α-glucosidase and their antibacterial properties were investigated. The α-glucosidase inhibitory activities of 5, 6, 7 and 9 were reported for the first time, with IC50 values ranging from 66.4 ± 6.7 to 185.9 ± 0.2 µM, as compared with acarbose (IC50 = 671.5 ± 0.2 µM). The molecular docking and molecular dynamics analysis of 5 with α-glucosidase further indicated that it may have a good binding ability with α-glucosidase. Both 9 and 12 exhibited moderate antibacterial activity against methicillin-resistant Staphylococcus aureus, with minimum inhibitory concentration (MIC) values of 16 µg/mL. These results indicate that 5, together with the naphthoquinone scaffold, has the potential to be further developed as a possible inhibitor of α-glucosidase.
Asunto(s)
Antibacterianos , Inhibidores de Glicósido Hidrolasas , Simulación del Acoplamiento Molecular , Naftoquinonas , Fenazinas , Streptomyces , alfa-Glucosidasas , Streptomyces/química , Naftoquinonas/química , Naftoquinonas/farmacología , Naftoquinonas/aislamiento & purificación , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/química , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Fenazinas/química , Fenazinas/farmacología , Fenazinas/aislamiento & purificación , Pruebas de Sensibilidad Microbiana , Endófitos/química , Estructura Molecular , Simulación de Dinámica Molecular , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacosRESUMEN
Acidic exopolysaccharide (EPS) was produced by a marine actinobacterium Streptomyces vinaceusdrappus strain AMG31 with the highest yield of 10.6 g/l. The synthesized EPS has an average molecular weight of 5.1 × 104 g/mol and contains arabinose, glucose, galacturonic acid (0.5:2:2 M ratio), with 39.77 % uronic acid residues and 18.8 % sulfate detected. EPS exhibited antioxidant activities with 93.8 % DPPH radical scavenging and 344.7 µg/mg total antioxidant capacity. It displayed anti-inflammatory effects by inhibiting 5-LOX and COX-2. Regarding the cytotoxic activity, the IC50 values are 301.6 ± 11.8, 260.8 ± 12.2, 29.4 ± 13.5, 351.3 ± 11.2, 254.1 ± 9.8, and 266.5 ± 10.4 µg/ml for PC-3, HEP-2, MCF-7, HCT-116, A-549, HepG-2 respectively, which indicate that the produced EPS does not have strong cytotoxic activities. Moreover, the EPS showed anti-Alzheimer activity via inhibition of the Butyrylcholinesterase enzyme, with the highest percentage of 84.5 % at 100 µg/ml. Interestingly, the EPS showed superior anti-obesity activity by inhibiting lipase enzyme with a rate of 95.3 % compared to orlistat as a positive control (96.8 %) at a concentration of 1000 µg/ml. Additionally, the produced EPS displayed the highest anti-diabetic properties by inhibiting α-amylase (IC50 31.49 µg/ml) and α-glucosidase (IC50 6.48 µg/ml), suggesting antidiabetic potential analogous to acarbose. EPS exhibited promising antibacterial and antibiofilm activity against a wide range of Gram-positive and Gram-negative pathogenic bacteria.
Asunto(s)
Antioxidantes , Polisacáridos Bacterianos , Streptomyces , Humanos , Polisacáridos Bacterianos/farmacología , Polisacáridos Bacterianos/química , Polisacáridos Bacterianos/aislamiento & purificación , Streptomyces/química , Antioxidantes/farmacología , Antioxidantes/química , Línea Celular Tumoral , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antineoplásicos/farmacología , Antineoplásicos/químicaRESUMEN
Nipah virus (NiV) remains a significant global concern due to its impact on both the agricultural industry and human health, resulting in substantial economic and health consequences. Currently, there is no cure or commercially available vaccine for the virus. Therefore, it is crucial to prioritize the discovery of new and effective treatment options to prevent its continued spread. Streptomyces spp. are rich sources of metabolites known for their bioactivity against certain diseases; however, their potential as antiviral drugs against the Nipah virus remain unexplored. In this study, 6524 Streptomyces spp. metabolites were screened through in silico methods for their inhibitory effects against the Nipah virus matrix (NiV-M) protein, which assists in virion assembly of Nipah virus. Different computer-aided tools were utilized to carry out the virtual screening process: ADMET profiling revealed 913 compounds with excellent safety and efficacy profiles, molecular docking predicted the binding poses and associated docking scores of the ligands in their respective targets, MD simulations confirmed the binding stability of the top ten highest-scoring ligands in a 100â¯ns all-atom simulation, PCA elucidated simulation convergence, and MMPB(GB)SA calculations estimated the binding energies of the final candidate compounds and determined the key residues crucial for complex formation. Using in silico methods, we identified six metabolites targeting the main substrate-binding site and five targeting the dimerization site that exhibited excellent stability and strong binding affinity. We recommend testing these compounds in the next stages of drug development to confirm their effectiveness as therapeutic agents against Nipah virus.
Asunto(s)
Antivirales , Simulación del Acoplamiento Molecular , Virus Nipah , Streptomyces , Proteínas de la Matriz Viral , Virus Nipah/efectos de los fármacos , Virus Nipah/metabolismo , Antivirales/farmacología , Antivirales/química , Streptomyces/química , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas de la Matriz Viral/metabolismo , Proteínas de la Matriz Viral/química , Ensayos Analíticos de Alto Rendimiento , Evaluación Preclínica de Medicamentos , Simulación de Dinámica Molecular , Pruebas de Sensibilidad Microbiana , Humanos , Estructura MolecularRESUMEN
Actinobacteria, pervasive in aquatic and terrestrial environments, exhibit a filamentous morphology, possess DNA with a specific G + C content and production of numerous secondary metabolites. This study, focused on actinobacteria isolated from marine seagrass, investigating their antibacterial activity against fish pathogens. Among 28 isolates, Streptomyces argenteolus TMA13 displayed the maximum zone of inhibition against fish pathogens-Aeromonas hydrophila (10 mm), Aeromonas caviae (22 mm), Edwardsiella tarda (17 mm), Vibrio harveyi (22 mm) and Vibrio anguillarum (12 mm) using the agar plug method. Optimization of this potent strain involved with various factors, including pH, temperature, carbon source and salt condition to enhance both yield production and antibacterial efficacy. In anti-biofilm assay shows the maximum percentage of inhibition while increasing concentration of TMA13 extract. Minimal Inhibitory Concentration (MIC) and Minimal Bactericidal Concentration (MBC) assays with TMA13 crude extract demonstrated potent activity against fish pathogens at remarkably low concentrations. Time-kill kinetics assay showcased growth curve variations over different time intervals for all fish pathogens treated with a 100 µg/ml concentration of crude extract, indicating a decline in cells viability and progression into the death phase. Additionally, fluorescence microscopic visualization of bacterial cells exposed to the extracts emitting green and red fluorescence, enabling live-dead cell differentiation was also studied. Further characterization of the crude extract through GC-MS and FT-IR analyses performed and identified secondary metabolites with functional groups exhibiting significant antibacterial activity. This study elucidates the capacity of Streptomyces argenteolus TMA13 to enhance the production of antibiotic compounds effective against fish pathogens.
Asunto(s)
Antibacterianos , Enfermedades de los Peces , Pruebas de Sensibilidad Microbiana , Streptomyces , Streptomyces/química , Streptomyces/metabolismo , Animales , Antibacterianos/farmacología , Enfermedades de los Peces/microbiología , Peces/microbiología , Cinética , Vibrio/efectos de los fármacos , Biopelículas/efectos de los fármacosRESUMEN
Heterologous expression of an atr terpenoid gene cluster derived from Streptomyces atratus Gö66 in S. albus J1074 led to the discovery of three novel labdane diterpenoids featuring an unprecedented 6/6/5-fused tricyclic skeleton, designated as atralabdans A-C (1-3), along with a known compound, labdanmycin A. Compounds 1-3 were identified through extensive spectroscopic analysis, including NMR calculations with DP4+ probability analysis, and a comparative assessment of experimental and theoretical electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway for these compounds was proposed. Compounds 1-3 exhibited inhibitory activity against the human neurotropic coxsackievirus B3 (CVB3); 1 was the most potent, surpassing the positive control ribavirin with a higher therapeutic index.
Asunto(s)
Antivirales , Microbiología del Suelo , Streptomyces , Streptomyces/química , Streptomyces/genética , Antivirales/farmacología , Antivirales/química , Estructura Molecular , Diterpenos/farmacología , Diterpenos/química , Humanos , Enterovirus Humano B/efectos de los fármacos , Familia de MultigenesRESUMEN
Various eco-friendly techniques are being researched for synthesizing ZnO-NPs, known for their bioactivity. This study aimed at biosynthesizing ZnO-NPs using Streptomyces baarnensis MH-133, characterizing their physicochemical properties, investigating antibacterial activity, and enhancement of their efficacy by combining them with a water-insoluble active compound (Ka) in a nanoemulsion form. Ka is a pure compound of 9-Ethyl-1,4,6,9,10-pentahydroxy-7,8,9,10-tetrahydrotetracene-5,12-dione obtained previously from our strain of Streptomyces baarnensis MH-133. Biosynthesized ZnO-NPs employing Streptomyces baarnensis MH-133 filtrate and zinc sulfate (ZnSO4.7H2O) as a precursor were purified and characterized by physicochemical investigation. High-resolution-transmission electron microscopy (HR-TEM) verified the effective biosynthesis of ZnO-NPs (size < 12 nm), whereas dynamic light scattering (DLS) analysis showed an average size of 17.5 nm. X-ray diffraction (XRD) exhibited characteristic diffraction patterns that confirmed crystalline structure. ZnO-NPs efficiently inhibited both Gram-positive and Gram-negative bacteria (MICs: 31.25-125 µg/ml). The pure compound (Ka) was combined with ZnO-NPs to improve effectiveness and reduce dose using checkerboard microdilution. Niteen treatments of Ka and ZnO-NPs combinations obtained by checkerboard matrix inhibited Klebsiella pneumonia. Eleven combinations had fractional inhibitory concentration index (FICi) between 1.03 and 2, meaning indifferent, another five combinations resulted from additive FICi (0.625-1) and only one combination with FICi of 0.5, indicating synergy. In the case of methicillin-resistant S. aureus (MRSA), Ka-ZnO-NPs combinations yielded 23 treatments with varying degrees of interaction. The results showed eleven treatments with indifferent interaction, eight additive interactions, and two synergies with FICi of 0.5 and 0.375. The combinations that exhibited synergy action were transformed into a nanoemulsion form to improve their solubility and bioavailability. The HR-TEM analysis of the nanoemulsion revealed spherical oil particles with a granulated core smaller than 200 nm and no signs of aggregation. Effective dispersion was confirmed by DLS analysis which indicated that Ka-ZnO-NPs nanoemulsion droplets have an average size of 53.1 nm and a polydispersity index (PI) of 0.523. The killing kinetic assay assessed the viability of methicillin-resistant Staphylococcus aureus (MRSA) and K. pneumonia post-treatment with Ka-ZnO-NPs combinations either in non-formulated or nanoemulsion form. Results showed Ka-ZnO-NPs combinations show concentration and time-dependent manner, with higher efficacy in nanoemulsion form. The findings indicated that Ka-ZnO-NPs without formulation at MIC values killed K. pneumonia after 24 h but not MRSA. Our nanoemulsion loaded with the previously mentioned combinations at MIC value showed bactericidal effect at MIC concentration of Ka-ZnO-NPs combination after 12 and 18 h of incubation against MRSA and K. pneumonia, respectively, compared to free combinations. At half MIC value, nanoemulsion increased the activity of the combinations to cause a bacteriostatic effect on MRSA and K. pneumonia after 24 h of incubation. The free combination showed a bacteriostatic impact for 6 h before the bacteria regrew to increase log10 colony forming unit (CFU)/ml over the initial level. Similarly, the cytotoxicity study revealed that the combination in nanoemulsion form decreased the cytotoxicity against kidney epithelial cells of the African green monkey (VERO) cell line. The IC50 for Ka-ZnO-NPs non-formulated treatment was 8.17/1.69 (µg/µg)/ml, but in nano-emulsion, it was 22.94 + 4.77 (µg/µg)/mL. In conclusion, efficient Ka-ZnO-NPs nanoemulsion may be a promising solution for the fighting of ESKAPE pathogenic bacteria according to antibacterial activity and low toxicity.
Asunto(s)
Antibacterianos , Tecnología Química Verde , Pruebas de Sensibilidad Microbiana , Streptomyces , Óxido de Zinc , Óxido de Zinc/farmacología , Óxido de Zinc/química , Streptomyces/metabolismo , Streptomyces/química , Antibacterianos/farmacología , Antibacterianos/química , Tecnología Química Verde/métodos , Humanos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Nanopartículas del Metal/química , Nanopartículas/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Klebsiella pneumoniae/efectos de los fármacosRESUMEN
Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is the first-line method for the rapid identification of most cultured microorganisms. As for Streptomyces strains, MALDI-TOF MS identification is complicated by the characteristic incrustation of colonies in agar and the strong cell wall of Actinomycetes cells requiring the use of alternative protein extraction protocols. In this study, we developed a specific protocol to overcome these difficulties for the MALDI-TOF MS identification of Actinomycetes made on solid medium. This protocol includes incubation of colony removed from agar plate with the beta-agarase enzyme, followed by a mechanical lysis and two washes by phosphate buffer and ethanol. Twenty-four Streptomyces and two Lentzea strains isolated from Algerian desertic soils were first identified by 16S rRNA sequencing as gold standard method, rpoB gene was used as a secondary gene target when 16S rRNA did not allow species identification. In parallel the isolates were identified by using the MALDI-TOF MS protocol as reported. After the expansion of the database with the inclusion of this MSPS, the strains were analyzed again in MALDI Biotyper, and all were identified. This work demonstrates that the rapid identification of Actinomycetes can be obtained without protein extraction step frequently used in MALDI-TOF mass spectrometry with this type of microorganisms.
Asunto(s)
Actinobacteria , ARN Ribosómico 16S , Microbiología del Suelo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , ARN Ribosómico 16S/genética , Argelia , Actinobacteria/aislamiento & purificación , Actinobacteria/genética , Actinobacteria/clasificación , Actinobacteria/química , ADN Bacteriano/genética , Streptomyces/aislamiento & purificación , Streptomyces/genética , Streptomyces/clasificación , Streptomyces/química , Proteínas Bacterianas/genética , ARN Polimerasas Dirigidas por ADN/genética , Medios de Cultivo/química , Análisis de Secuencia de ADN , Técnicas Bacteriológicas/métodos , Glicósido HidrolasasRESUMEN
New diterpenoids are accessible from non-natural FPP derivatives as substrates for an enzymatic elongation cyclization cascade using the geranylgeranyl pyrophosphate synthase (GGPPS) from Streptomyces cyaneofuscatus and the spata-13,17-diene synthase (SpS) from Streptomyces xinghaiensis. This approach led to four new biotransformation products including three new cyclododecane cores and a macrocyclic ether. For the first time, a 1,12-terpene cyclization was observed when shifting the central olefinic double bond toward the geminial methyl groups creating a nonconjugated 1,4-diene.
Asunto(s)
Transferasas Alquil y Aril , Dimetilaliltranstransferasa , Diterpenos , Streptomyces , Diterpenos/química , Diterpenos/metabolismo , Dimetilaliltranstransferasa/metabolismo , Dimetilaliltranstransferasa/química , Streptomyces/enzimología , Streptomyces/química , Transferasas Alquil y Aril/metabolismo , Transferasas Alquil y Aril/química , Estructura Molecular , Ciclización , Fosfatos de Poliisoprenilo/química , Fosfatos de Poliisoprenilo/metabolismo , BiotransformaciónRESUMEN
Ten undocumented carbazole derivatives (2-11) along with the reported analogue (1) were isolated from the mangrove-derived Streptomyces sp. OUCMDZ-5511, cultured with NaBr-supplemented liquid medium. Compounds 1-7 are brominated carbazoles, and 8, 10, and 11 feature an additional thiazole or 2,3-dihydro-1,4-oxathiine rings, respectively. Their structures were identified through spectroscopic techniques, computational chemistry, and X-ray crystallography. Notably, compounds 6 and 8 effectively inhibited immune cell migration, indicating anti-inflammatory activity in vivo, potentially via Myd88/Nf-κB pathways, as suggested for compound 6.
Asunto(s)
Carbazoles , Streptomyces , Streptomyces/química , Carbazoles/química , Carbazoles/farmacología , Carbazoles/aislamiento & purificación , Estructura Molecular , Cristalografía por Rayos X , Bromo/química , Azufre/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/aislamiento & purificación , Biología Marina , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , AnimalesRESUMEN
A bioassay-guided chemical investigation of a bacterium, Streptomyces sp. CMB-MRB032, isolated from sheep feces collected near Bathurst, Victoria, Australia, yielded the known polyketide antimycins A4a (1) and A2a (2) as potent inhibitors of Dirofilaria immitis (heartworm) microfilaria (mf) motility (EC50 0.0013-0.0021 µg/mL), along with the octapeptide surugamide A (3) and the new N-methylated analog surugamide K (4). With biological data suggesting surugamides may also exhibit activity against D. immitis, a GNPS molecular network analysis of a library of microbes sourced from geographically diverse Australian ecosystems identified a further five taxonomically and chemically distinct surugamide producers. Scaled-up cultivation of one such producer, Streptomyces sp. CMB-M0112 isolated from a marine sediment collected at Shorncliff, Qld, Australia, yielded 3 along with the new acyl-surugamides A1-A4 (5-8). Solid-phase peptide synthesis provided additional synthetic analogs, surugamides S1-S3 (9-11), while derivatization of 3 returned the semi-synthetic surugamide S4 (12) and acyl-surugamides AS1-AS3 (13-15). The natural acyl-surugamide A3 (7) and semi-synthetic acyl-surugamide AS3 (15) were shown to selectively inhibit D. immitis mf motility (EC50 3.3-3.4 µg/mL), however, unlike antimycins 1 and 2, were inactive against the gastrointestinal nematode Haemonchus contortus L1-L3 larvae (EC50 > 25 µg/mL) and were not cytotoxic to mammalian cells (human colorectal carcinoma SW620, IC50 > 30 µg/mL). A structure-activity relationship (SAR) study on the surugamides 3-15 revealed that selective acylation of the Lys3-ε-NH2 correlates with anthelmintic activity.
Asunto(s)
Dirofilaria immitis , Streptomyces , Animales , Streptomyces/química , Dirofilaria immitis/efectos de los fármacos , Australia , Ovinos , Heces/parasitología , Heces/microbiologíaRESUMEN
Recent advances in whole genome sequencing have revealed an immense microbial potential for the production of therapeutic small molecules, even from well-known producers. To access this potential, we subjected prominent antimicrobial producers to alternative antiproliferative assays using persistent cancer cell lines. Described herein is our discovery of hirocidins, novel secondary metabolites from Streptomyces hiroshimensis with antiproliferative activities against colon and persistent breast cancer cells. Hirocidin A is an unusual nine-membered carbocyclic maleimide and hirocidins B and C are relatives with an unprecedented, bridged azamacrocyclic backbone. Mode of action studies show that hirocidins trigger mitochondrion-dependent apoptosis by inducing expression of the key apoptotic effector caspase-9. The discovery of new cytotoxins contributes to scaffold diversification in anticancer drug discovery and the reported modes of action and concise total synthetic route for variant A set the stage for unraveling specific targets and biochemical interactions of the hirocidins.
Asunto(s)
Antineoplásicos , Apoptosis , Mitocondrias , Streptomyces , Streptomyces/metabolismo , Streptomyces/química , Humanos , Apoptosis/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Estructura MolecularRESUMEN
Potato common scab (PCS) is a widespread plant disease that lacks effective control measures. Using a small molecule elicitor, we activate the production of a novel class of polyketide antibiotics, streptolateritic acids A-D, in Streptomyces sp. FXJ1.172. These compounds show a promising control efficacy against PCS and an unusual acyclic pentacarboxylic acid structure. A gene cluster encoding a type I modular polyketide synthase is identified to be responsible for the biosynthesis of these metabolites. A cytochrome P450 (CYP) and an aldehyde dehydrogenase (ADH) encoded by two genes in the cluster are proposed to catalyze iterative oxidation of the starter-unit-derived methyl group and three of six branching methyl groups to carboxylic acids during chain assembly. Our findings highlight how activation of silent biosynthetic gene clusters can be employed to discover completely new natural product classes able to combat PCS and new types of modular polyketide synthase-based biosynthetic machinery.
Asunto(s)
Proteínas Bacterianas , Familia de Multigenes , Enfermedades de las Plantas , Sintasas Poliquetidas , Solanum tuberosum , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Streptomyces/química , Enfermedades de las Plantas/microbiología , Solanum tuberosum/metabolismo , Sintasas Poliquetidas/genética , Sintasas Poliquetidas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/biosíntesis , Vías Biosintéticas , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismoRESUMEN
A new dimeric C-glycoside polyketide chrysomycin F (1), along with four new monomeric compounds, chrysomycins G (2), H (3), I (4), J (5), as well as three known analogues, chrysomycins A (6), B (7), and C (8), were isolated and characterised from a strain of Streptomyces sp. obtained from a sediment sample collected from the South China Sea. Their structures were determined by detailed spectroscopic analysis. Chrysomycin F contains two diastereomers, whose structures were further elucidated by a biomimetic [2 + 2] photodimerisation of chrysomycin A. Chrysomycins B and C showed potent anti-tuberculosis activity against both wild-type Mycobacterium tuberculosis and a number of clinically isolated MDR M. tuberculosis strains.
Asunto(s)
Antituberculosos , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis , Policétidos , Streptomyces , Streptomyces/química , Streptomyces/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Antituberculosos/farmacología , Antituberculosos/química , Antituberculosos/aislamiento & purificación , Policétidos/farmacología , Policétidos/química , Policétidos/aislamiento & purificación , Glicósidos/química , Glicósidos/farmacología , Glicósidos/aislamiento & purificación , China , Estructura Molecular , Antraquinonas/farmacología , Antraquinonas/química , Antraquinonas/aislamiento & purificaciónRESUMEN
BACKGROUND: Antimicrobial resistance (AMR) is a serious worldwide public health concern that needs immediate action. Probiotics could be a promising alternative for fighting antibiotic resistance, displaying beneficial effects to the host by combating diseases, improving growth, and stimulating the host immune responses against infection. This study was conducted to evaluate the probiotic, antibacterial, and antibiofilm potential of Streptomyces levis strain HFM-2 isolated from the healthy human gut. RESULTS: In vitro antibacterial activity in the cell-free supernatant of S. levis strain HFM-2 was evaluated against different pathogens viz. K. pneumoniae sub sp. pneumoniae, S. aureus, B. subtilis, VRE, S. typhi, S. epidermidis, MRSA, V. cholerae, M. smegmatis, E. coli, P. aeruginosa and E. aerogenes. Further, the ethyl acetate extract from S. levis strain HFM-2 showed strong biofilm inhibition against S. typhi, K. pneumoniae sub sp. pneumoniae, P. aeruginosa and E. coli. Fluorescence microscopy was used to detect biofilm inhibition properties. MIC and MBC values of EtOAc extract were determined at 500 and 1000 µg/mL, respectively. Further, strain HFM-2 showed high tolerance in gastric juice, pancreatin, bile, and at low pH. It exhibited efficient adhesion properties, displaying auto-aggregation (97.0%), hydrophobicity (95.71%, 88.96%, and 81.15% for ethyl acetate, chloroform and xylene, respectively), and showed 89.75%, 86.53%, 83.06% and 76.13% co-aggregation with S. typhi, MRSA, S. pyogenes and E. coli, respectively after 60 min of incubation. The S. levis strain HFM-2 was susceptible to different antibiotics such as tetracycline, streptomycin, kanamycin, ciprofloxacin, erythromycin, linezolid, meropenem, amikacin, gentamycin, clindamycin, moxifloxacin and vancomycin, but resistant to ampicillin and penicillin G. CONCLUSION: The study shows that S. levis strain HFM-2 has significant probiotic properties such as good viability in bile, gastric juice, pancreatin environment, and at low pH; proficient adhesion properties, and antibiotic susceptibility. Further, the EtOAc extract of Streptomyces levis strain HFM-2 has a potent antibiofilm and antibacterial activity against antibacterial-resistant clinical pathogens.
Asunto(s)
Antibacterianos , Biopelículas , Pruebas de Sensibilidad Microbiana , Probióticos , Streptomyces , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Humanos , Probióticos/farmacología , Streptomyces/fisiología , Streptomyces/clasificación , Streptomyces/aislamiento & purificación , Streptomyces/química , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Bacterias/clasificación , Tracto Gastrointestinal/microbiologíaRESUMEN
Mangrove derived actinomycetes are a rich reservoir of bioactive natural products and play important roles in pharmaceutical chemistry. In a screen of actinomycetes from mangrove rhizosphere sedimental environments, the isolated strain Streptomyces sp. SCSIO 40068 displayed strong antibacterial activity. Further fractionation of the extract yielded four new compounds kebanmycins A-D (1-4) and two known analogues FD-594 (5) and the aglycon (6). The structures of 1-6 were determined based on extensive spectroscopic data and single-crystal X-ray diffraction analysis. 1-3 featured a fused pyranonaphthaxanthene as an integral part of a 6/6/6/6/6/6 polycyclic motif, and showed bioactivity against a series of Gram-positive bacteria and cytotoxicity to several human tumor cells. In addition, the kebanmycins biosynthetic gene cluster (keb) was identified in Streptomyces sp. SCSIO 40068, and KebMT2 was biochemically characterized as a tailoring sugar-O-methyltransferase, leading to a proposed biosynthetic route to 1-6. This study paves the way to further investigate 1 as a potential lead compound.
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Antibacterianos , Streptomyces , Humanos , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Ensayos de Selección de Medicamentos Antitumorales , Bacterias Grampositivas/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Familia de Multigenes , Rhizophoraceae/microbiología , Streptomyces/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacologíaRESUMEN
A study targeting novel antifungal metabolites identified potent in vitro antifungal activity against key plant pathogens in acetone extracts of Streptomyces sp. strain CA-296093. Feature-based molecular networking revealed the presence in this extract of antimycin-related compounds, leading to the isolation of four new compounds: escuzarmycins A-D (1-4). Extensive structural elucidation, employing 1D and 2D NMR, high-resolution mass spectrometry, Marfey's analysis, and NOESY correlations, confirmed their structures. The bioactivity of these compounds was tested against six fungal phytopathogens, and compounds 3 and 4 demonstrated strong efficacy, particularly against Zymoseptoria tritici, with compound 3 exhibiting the highest potency (EC50: 11 nM). Both compounds also displayed significant antifungal activity against Botrytis cinerea and Colletotrichum acutatum, with compound 4 proving to be the most potent. Despite moderate cytotoxicity against the human cancer cell line HepG2, compounds 3 and 4 emerge as promising fungicides for combating Septoria tritici blotch, anthracnose, and gray mold.
Asunto(s)
Ascomicetos , Colletotrichum , Fungicidas Industriales , Enfermedades de las Plantas , Streptomyces , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Ascomicetos/efectos de los fármacos , Ascomicetos/química , Streptomyces/química , Streptomyces/metabolismo , Humanos , Colletotrichum/efectos de los fármacos , Botrytis/efectos de los fármacos , Estructura MolecularRESUMEN
Synthetic routes to geosmin and its enantiomer are well established, but the enantioselective synthesis of stereoisomers of geosmin is unknown. Here a stereoselective synthesis of all stereoisomers of geosmin is reported, yielding all compounds in high enantiomeric purity. Furthermore, the stereoselective synthesis of a geosmin derivative isolated from a mangrove associated streptomycete was performed, establishing the absolute configuration of the natural product. Finally, a new side product of the geosmin synthase from Streptomyces ambofaciens was isolated and its structure was elucidated by NMR spectroscopy. The absolute configuration of this new compound was determined through a stereoselective synthesis.