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Members of the bacterial phylum Planctomycetota have recently emerged as promising and for the most part untapped sources of novel bioactive compounds. The characterization of more than 100 novel species in the last decade stimulated recent bioprospection studies that start to unveil the chemical repertoire of the phylum. In this study, we performed systematic bioinformatic analyses based on the genomes of all 131 described members of the current phylum focusing on the identification of type III polyketide synthase (PKS) genes. Type III PKSs are versatile enzymes involved in the biosynthesis of a wide array of structurally diverse natural products with potent biological activities. We identified 96 putative type III PKS genes of which 58 are encoded in an operon with genes encoding a putative oxidoreductase and a methyltransferase. Sequence similarities on protein level and the genetic organization of the operon point towards a functional link to the structurally related hierridins recently discovered in picocyanobacteria. The heterologous expression of planctomycetal type III PKS genes from strains belonging to different families in an engineered Corynebacterium glutamicum strain led to the biosynthesis of pentadecyl- and heptadecylresorcinols. Phenotypic assays performed with the heterologous producer strains and a constructed type III PKS gene deletion mutant suggest that the natural function of the identified compounds differs from that confirmed in other bacterial alkylresorcinol producers. KEY POINTS: ⢠Planctomycetal type III polyketide synthases synthesize long-chain alkylresorcinols. ⢠Phylogenetic analyses suggest an ecological link to picocyanobacterial hierridins. ⢠Engineered C. glutamicum is suitable for an expression of planctomycete-derived genes.
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Aciltransferasas , Planctomicetos , Humanos , Filogenia , OperónRESUMEN
The cosmopolitan marine Roseobacter clade is of global biogeochemical importance. Members of this clade produce sulfur-containing amino lipids (SALs) involved in biofilm formation and marine surface colonization processes. Despite their physiological relevance and abundance, SALs have only been explored through genomic mining approaches and lipidomic studies based on mass spectrometry, which left the relative and absolute structures of SALs unresolved, hindering progress in biochemical and functional investigations. Herein, we report the structural revision of a new group of SALs, which we named cysteinolides, using a combination of analytical techniques, isolation and degradation experiments and total synthetic efforts. Contrary to the previously proposed homotaurine-based structures, cysteinolides are composed of an N,O-acylated cysteinolic acid-containing head group carrying various different (α-hydroxy)carboxylic acids. We also performed the first validated targeted-network based analysis, which allowed us to map the distribution and structural diversity of cysteinolides across bacterial lineages. Beyond offering structural insight, our research provides SAL standards and validated analytical data. This information holds significance for forthcoming investigations into bacterial sulfonolipid metabolism and biogeochemical nutrient cycling within marine environments.
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Lípidos , Lípidos/química , Roseobacter/metabolismo , Roseobacter/química , Estructura Molecular , Organismos Acuáticos/químicaRESUMEN
Toxicity has evolved multiple times across the tree of life and serves important functions related to hunting, defence and parasite deterrence. Toxins are produced either in situ by the toxic organism itself or associated symbionts, or acquired through diet. The ability to exploit toxins from external sources requires adaptations that prevent toxic effects on the consumer (autoresistance). Here, we examine genomic adaptations that could facilitate autoresistance to the diet-acquired potent neurotoxic alkaloid batrachotoxin (BTX) in New Guinean toxic birds. Our work documents two new toxic bird species and shows that toxic birds carry multiple mutations in the SCN4A gene that are under positive selection. This gene encodes the most common vertebrate muscle Nav channel (Nav1.4). Molecular docking results indicate that some of the mutations that are present in the pore-forming segment of the Nav channel, where BTX binds, could reduce its binding affinity. These mutations should therefore prevent the continuous opening of the sodium channels that BTX binding elicits, thereby preventing muscle paralysis and ultimately death. Although these mutations are different from those present in Neotropical Phyllobates poison dart frogs, they occur in the same segments of the Nav1.4 channel. Consequently, in addition to uncovering a greater diversity of toxic bird species than previously known, our work provides an intriguing example of molecular-level convergent adaptations allowing frogs and birds to ingest and use the same neurotoxin. This suggests that genetically modified Nav1.4 channels represent a key adaptation to BTX tolerance and exploitation across vertebrates.
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Covering: findings from early 1980s until early 2022Microbial-derived cues of marine biofilms induce settlement and metamorphosis of marine organisms, a process responsible for the emergence of diverse flora and fauna in marine habitats. Although this phenomenon is known for more than 80 years, the research field has only recently gained much momentum. Here, we summarize the currently existing biochemical and microbial knowledge about microbial signalling molecules, con-specific signals, and synthetic compounds that induce or prevent recruitment, settlement, and metamorphosis in invertebrate larvae. We discuss the possible modes of action and conclude with perspectives for future research directions in the field of marine chemical ecology.
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Organismos Acuáticos , Metamorfosis Biológica , Animales , Biopelículas , Larva , Biología MarinaRESUMEN
Covering: September 1972 to December 2020Explorations of complex symbioses have often elucidated a plethora of previously undescribed chemical compounds that may serve ecological functions in signalling, communication or defence. A case in point is the subfamily of termites that cultivate a fungus as their primary food source and maintain complex bacterial communities, from which a series of novel compound discoveries have been made. Here, we summarise the origins and types of 375 compounds that have been discovered from the symbiosis over the past four decades and discuss the potential for synergistic actions between compounds within the complex chemical mixtures in which they exist. We go on to highlight how vastly underexplored the diversity and geographic distribution of the symbiosis is, which leaves ample potential for natural product discovery of compounds of both ecological and medical importance.
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Isópteros , Agricultura , Animales , Hongos , Isópteros/microbiología , Filogenia , SimbiosisRESUMEN
δ-Hydroxy-ß-keto esters and δ,ß-dihydroxy esters are characteristic structural motifs of statin-type natural products and drug candidates. Here, we describe the synthesis of functionalized δ-hydroxy-ß-keto esters in good yields and excellent enantioselectivities using Chan's diene and modified Mukaiyama-aldol reaction conditions. Diastereoselective reduction of δ,ß-dihydroxy esters afforded the respective syn- and anti-diols, and saponification yielded the corresponding acids. All products were evaluated for their anti-inflammatory properties, which uncovered a surprising structure-activity relationship.
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Productos Biológicos , Ésteres , Antiinflamatorios/farmacología , Polienos , Relación Estructura-ActividadRESUMEN
We have analyzed the abundance of bacterial sulfonosphingolipids, including rosette-inducing factors (RIFs), in seven bacterial prey strains by using high-resolution tandem mass spectrometry (HRMS2 ) and molecular networking (MN) within the Global Natural Product Social Molecular Networking (GNPS) web platform. Six sulfonosphingolipids resembling RIFs were isolated and their structures were elucidated based on comparative MS and NMR studies. Here, we also report the first total synthesis of two RIF-2 diastereomers and one congener in 15 and eight synthetic steps, respectively. For the total synthesis of RIF-2 congeners, we employed a decarboxylative cross-coupling reaction to synthesize the necessary branched α-hydroxy fatty acids, and the Garner-aldehyde approach to generate the capnine base carrying three stereogenic centers. Bioactivity studies in the choanoflagellate Salpingoeca rosetta revealed that the rosette inducing activity of RIFs is inhibited dose dependently by the co-occurring sulfonosphingolipid sulfobacins D and F and that activity of RIFs is specific for isolates obtained from Algoriphagus.
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Bacteroidetes , Coanoflagelados , Esfingolípidos/química , Bacterias , Bacteroidetes/química , Coanoflagelados/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas en TándemRESUMEN
In this study, we analyzed if Actinomadura sp. RB99 produces siderophores that that could be responsible for the antimicrobial activity observed in co-cultivation studies. Dereplication of high-resolution tandem mass spectrometry (HRMS/MS) and global natural product social molecular networking platform (GNPS) analysis of fungus-bacterium co-cultures resulted in the identification of five madurastatin derivatives (A1, A2, E1, F, and G1), of which were four new derivatives. Chemical structures were unambiguously confirmed by HR-ESI-MS, 1D and 2D NMR experiments, as well as MS/MS data and their absolute structures were elucidated based on Marfey's analysis, DP4+ probability calculation and total synthesis. Structure analysis revealed that madurastatin E1 (2) contained a rare 4-imidazolidinone cyclic moiety and madurastatin A1 (5) was characterized as a Ga3+ -complex. The function of madurastatins as siderophores was evaluated using the fungal pathogen Cryptococcus neoformans as model organism. Based on homology models, we identified the putative NRPS-based gene cluster region of the siderophores in Actinomadura sp. RB99.
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Isópteros , Sideróforos , Actinomadura , Animales , Isópteros/microbiología , Espectroscopía de Resonancia Magnética , Sideróforos/química , Espectrometría de Masas en TándemRESUMEN
Cultures of a termite-associated and a free-living member of the fungal genus Podaxis, revived from spores maintained in century-old herbarium collections, were analyzed for their insecticidal and antimicrobial effects. Their secondary metabolomes were explored to uncover possible adaptive mechanisms of termite association, and dereplication of LC-HRMS/MS data sets led to the isolation of podaxisterols A-D (1-4), modified ergosterol derivatives that result from a Diels-Alder reaction with endogenous nitrosyl cyanide. Chemical structures were determined based on HRMS/MS and NMR analyses as well as X-ray crystallography. The putative origin of the endogenous fungal nitrosyl cyanide and ergosterol derivatives is discussed based on results obtained from stable isotope experiments and in silico analysis. Our "omics"-driven analysis of this underexplored yet worldwide distributed fungal genus builds a foundation for studies on a potential metabolic adaptations to diverse lifestyles.
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Agaricales , Antiinfecciosos , Ergosterol , Insecticidas , Isópteros , Agaricales/química , Agaricales/metabolismo , Animales , Antiinfecciosos/química , Antiinfecciosos/aislamiento & purificación , Antiinfecciosos/farmacología , Ergosterol/análogos & derivados , Ergosterol/aislamiento & purificación , Ergosterol/farmacología , Insecticidas/química , Insecticidas/aislamiento & purificación , Insecticidas/farmacología , Isópteros/microbiología , Metabolómica , Óxidos de Nitrógeno/químicaRESUMEN
Sphingofungins are fungal natural products known to inhibit the biosynthesis of sphingolipids which play pivotal roles in various cell functions. Here, we report a short and flexible synthetic approach towards the sphingofungin family. Key step of the synthesis was a decarboxylative cross-coupling reaction of chiral sulfinyl imines with a functionalized tartaric acid derivative, which yielded the core motif of sphingofungins carrying four consecutive stereocenters and a terminal double bond. Subsequent metathesis reaction allowed for the introduction of different side chains of choice resulting in a total of eight sphingofungins, including for the first time sphingofunginâ C (eight steps from commercially available protected tartaric acid with an overall yield of 6 %) and sphingofunginâ A (ten steps). All newly synthesized derivatives were tested for their antifungal, cell-proliferative and antiparasitic activity unraveling their structure-activity relations.
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Aminoácidos , Ácidos Grasos InsaturadosRESUMEN
The choanoflagellate Salpingoeca rosetta is an important model system to study the evolution of multicellularity. In this study we developed a new, modular, and scalable synthesis of sulfonolipid IOR-1A (six steps, 27 % overall yield), which acts as bacterial inhibitor of rosette formation in S.â rosetta. The synthesis features a decarboxylative cross-coupling reaction of a sulfonic acid-containing tartaric acid derivative with alkyl zinc reagents. Synthesis of 15 modified IOR-1A derivatives, including fluorescent and photoaffinity-based probes, allowed quantification of IOR-1A, localization studies within S.â rosetta cells, and evaluation of structure-activity relations. In a proof of concept study, an inhibitory bifunctional probe was employed in proteomic profiling studies, which allowed to deduce binding partners in bacteria and S.â rosetta. These results showcase the power of synthetic chemistry to decipher the biochemical basis of cell differentiation processes within S.â rosetta.
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Coanoflagelados , Diferenciación Celular , Lípidos , Proteómica , Ácidos Sulfónicos , ZincRESUMEN
Aromatic prenylated metabolites have important biological roles and activities in all living organisms. Compared to their importance in all domains of life, we know relatively little about their substrate scopes and metabolic functions. Here, we describe a new UbiA-like prenyltransferase (Ptase) Ubi-297 encoded in a conserved operon of several bacterial taxa, including marine Flavobacteria and the genus Sacchromonospora. In silico analysis of Ubi-297 homologs indicated that members of this Ptase group are composed of several transmembrane α-helices and carry a conserved and distinct aspartic-rich Mg2+-binding domain. We heterologously produced UbiA-like Ptases from the bacterial genera Maribacter, Zobellia, and Algoriphagus in Escherichia coli. Investigation of their substrate scope uncovered the preferential farnesylation of quinoline derivatives, such as 8-hydroxyquinoline-2-carboxylic acid (8-HQA) and quinaldic acid. The results of this study provide new insights into the abundance and diversity of Ptases in marine Flavobacteria and beyond.
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Marine bacteria are excellent yet often underexplored sources of structurally unique bioactive natural products. In this review we cover the diversity of marine bacterial biomolecules and highlight recent studies on structurally novel natural products. We include different compound classes and discuss the latest progress related to their biosynthetic pathway analysis and engineering: examples range from fatty acids over terpenes to PKS, NRPS and hybrid PKS-NRPS biomolecules.
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Organismos Acuáticos , Bacterias/metabolismo , Productos Biológicos/metabolismo , Productos Biológicos/químicaRESUMEN
High-resolution tandem mass spectrometry (HR-MS2)-based metabolomic studies of Amycolatopsis saalfeldensis, isolated from the "Saalfelder Feengrotten" caves in Germany, led to the isolation of three ribosomally synthesized and post-translationally modified type II thiopeptides, saalfelduracin B-D (1-3) and the known saalfelduracin A (4). The structures of all four compounds were determined by comparative two-dimensional NMR analysis and high-resolution tandem mass spectrometry.
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Antiinfecciosos/farmacología , Cuevas/microbiología , Péptidos/farmacología , Amycolatopsis/química , Antiinfecciosos/aislamiento & purificación , Antibiosis , Productos Biológicos/aislamiento & purificación , Productos Biológicos/farmacología , Cromatografía Líquida de Alta Presión , Técnicas de Cocultivo , Alemania , Metabolómica , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptidos/aislamiento & purificación , Espectrometría de Masas en TándemRESUMEN
Herein, we report the targeted isolation and characterization of four linear nonribosomally synthesized tetrapeptides (pseudoxylaramide A-D) and two cyclic nonribosomal peptide synthetase-polyketide synthase-derived natural products (xylacremolide A and B) from the termite-associated stowaway fungus Pseudoxylaria sp. X187. The fungal strain was prioritized for further metabolic analysis based on its taxonomical position and morphological and bioassay data. Metabolic data were dereplicated based on high-resolution tandem mass spectrometry data and global molecular networking analysis. The structure of all six new natural products was elucidated based on a combination of 1D and 2D NMR analysis, Marfey's analysis and X-ray crystallography.
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Productos Biológicos/química , Descubrimiento de Drogas , Oligopéptidos/química , Péptidos Cíclicos/química , Policétidos/química , Termitomyces/química , Productos Biológicos/aislamiento & purificación , Cristalografía por Rayos X , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear Biomolecular , Oligopéptidos/aislamiento & purificación , Péptidos Cíclicos/aislamiento & purificación , Policétidos/aislamiento & purificación , EstereoisomerismoRESUMEN
Xylaria species are prolific natural product producers. Here, we report the characterization of a new glycosylated incisterol derivative, called xyloneside A (1) and two known lignans (2 and 3) from the ascomycetous Xylaria sp. FB. The structure of xyloneside A (1) was determined by 1D and 2D NMR spectroscopy, high-resolution electrospray ionization mass spectrometry and electronic circular dichroism measurements. Xyloneside A is composed of a 1,2,3,4,5,10,19-heptanorergosterane skeleton and a ß-D-mannopyranose moiety. This is the first report of an incisterol derivative from an Ascomycete. The biological effects of the isolated metabolites on cytotoxicity, autophagy, cell-migration, and angiogenesis were evaluated.
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Antineoplásicos/química , Xylariales/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Glicosilación , HumanosRESUMEN
The taxonomic positions of two novel aerobic, Gram-positive actinobacteria, designated strains RB29T and RB68T, were determined using a polyphasic approach. Based on 16S rRNA gene sequence analysis, the closest phylogenetic neighbours of RB29T were identified as Actinomadura rayongensis DSM 102126T (99.2â% similarity) and Actinomadura atramentaria DSM 43919T (98.7â%), and for strain RB68T was Actinomadura hibisca DSM 44148T (98.3â%). Digital DNA-DNA hybridization (dDDH) between RB29T and its closest phylogenetic neighbours, A. rayongensis DSM 102126T and A. atramentaria DSM 43919T, resulted in similarity values of 53.2â% (50.6-55.9â%) and 26.4â% (24.1-28.9â%), respectively. Additionally, the average nucleotide identity (ANI) was 93.2â% (94.0â%) for A. rayongensis DSM 102126T and 82.3â% (78.9â%) for A. atramentaria DSM 43919T. dDDH analysis between strain RB68T and A. hibisca DSM 44148T gave a similarity value of 24.5â% (22.2-27.0â%). Both strains, RB29T and RB68T, revealed morphological characteristics and chemotaxonomic features typical for the genus Actinomadura, such as the presence of meso-diaminopimelic acid in the cell wall, galactose and glucose as major sugar components within whole-cell hydrolysates and the absence of mycolic acids. The major phospholipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. Predominant menaquinones were MK-9(H6) and MK-9(H8) for RB29T and MK-9(H4) and MK-9(H6) for RB68T. The main fatty acids were identified as 10-methyloctadecanoic acid (10-methyl C18:0), 14-methylpentadecanoic acid (iso-C16:0), hexadecanoic acid (C16:0) and cis-9-octadecanoic acid (C18â:â1 ω9c). Here, we propose two novel species of the genus Actinomadura: Actinomadura rubteroloni sp. nov. with the type strain RB29T (=CCUG 72668T=NRRL B-65537T) and Actinomadura macrotermitis sp. nov. with the type strain RB68T (=CCUG 72669T=NRRL B-65538T).
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Actinobacteria/clasificación , Isópteros/microbiología , Filogenia , Actinobacteria/aislamiento & purificación , Animales , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácido Diaminopimélico/química , Ácidos Grasos/química , Microbioma Gastrointestinal , Hibridación de Ácido Nucleico , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Sudáfrica , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMEN
The taxonomic position of a novel aerobic, Gram-positive actinobacteria, designated strain RB5T, was determined using a polyphasic approach. The strain, isolated from the gut of the fungus-farming termite Macrotermes natalensis, showed morphological, physiological and chemotaxonomic properties typical of the genus Streptomyces. Based on 16S rRNA gene sequence analysis, the closest phylogenetic neighbour of RB5T was Streptomyces polyrhachis DSM 42102T (98.87â%). DNA-DNA hybridization experiments between strain RB5T and S. polyrhachis DSM 42102T resulted in a value of 27.4â% (26.8â%). The cell wall of strain RB5T contained ll-diaminopimelic acid as the diagnostic amino acid. Mycolic acids and diagnostic sugars in whole-cell hydrolysates were not detected. The strain produced the following major phospholipids: diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol-mannoside and phosphatidylserine. The menaquinone profile showed hexa- and octahydrogenated menaquinones containing nine isoprene units [MK-9(H6) and MK-9(H8)]. The strain exhibited a fatty acid profile containing the following major fatty acids: 12-methyltridecanoic acid (iso-C14â:â0) 12-methyltetradecanoic acid (anteiso-C15â:â0), 13-methyltetradecanoic acid (iso-C15â:â0) and 14-methylpentadecanoic acid (iso-C16â:â0). Here, we propose a novel species of the genus Streptomyces - Streptomyces smaragdinus with the type strain RB5T (=VKM Ac-2839T=NRRL B65539T).
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Isópteros/microbiología , Filogenia , Streptomyces/clasificación , Animales , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/química , Tracto Gastrointestinal/microbiología , Hibridación de Ácido Nucleico , Fosfolípidos/química , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , Sudáfrica , Streptomyces/aislamiento & purificación , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMEN
The taxonomic positions of two novel aerobic, Gram-stain-positive Actinobacteria, designated RB20T and RB56T, were determined using a polyphasic approach. Both were isolated from the fungus-farming termite Macrotermes natalensis. Results of 16S rRNA gene sequence analysis revealed that both strains are members of the genus Nocardia with the closest phylogenetic neighbours Nocardia miyunensis JCM12860T (98.9â%) and Nocardia nova DSM44481T (98.5â%) for RB20T and Nocardia takedensis DSM 44801T (98.3â%), Nocardia pseudobrasiliensis DSM 44290T (98.3â%) and Nocardia rayongensis JCM 19832T (98.2â%) for RB56T. Digital DNA-DNA hybridization (DDH) between RB20T and N. miyunensis JCM12860T and N. nova DSM 44481T resulted in similarity values of 33.9 and 22.0â%, respectively. DDH between RB56T and N. takedensis DSM44801T and N. pseudobrasiliensis DSM44290T showed similarity values of 20.7 and 22.3â%, respectively. In addition, wet-lab DDH between RB56T and N. rayongensis JCM19832T resulted in 10.2â% (14.5â%) similarity. Both strains showed morphological and chemotaxonomic features typical for the genus Nocardia, such as the presence of meso-diaminopimelic acid (A2pm) within the cell wall, arabinose and galactose as major sugar components within whole cell-wall hydrolysates, the presence of mycolic acids and major phospholipids (diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol), and the predominant menaquinone MK-8 (H4, ω-cyclo). The main fatty acids for both strains were hexadecanoic acid (C16â:â0), 10-methyloctadecanoic acid (10-methyl C18â:â0) and cis-9-octadecenoic acid (C18â:â1 ω9c). We propose two novel species within the genus Nocardia: Nocardia macrotermitis sp. nov. with the type strain RB20T (=VKM Ac-2841T=NRRL B65541T) and Nocardia aurantia sp. nov. with the type strain RB56T (=VKM Ac-2842T=NRRL B65542T).
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Isópteros/microbiología , Nocardia/clasificación , Filogenia , Animales , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácido Diaminopimélico/química , Ácidos Grasos/química , Microbioma Gastrointestinal , Nocardia/aislamiento & purificación , Fosfolípidos/química , ARN Ribosómico 16S/genética , Sudáfrica , Vitamina K 2/análogos & derivados , Vitamina K 2/químicaRESUMEN
Hepcidins, a group of antimicrobial peptides (AMPs), play a key role in the innate immune system of fishes and act against different pathogens. In this study, antimicrobial and immune-inflammatory activity of a synthetic EC-hepcidin1, previously identified from orange-spotted grouper, were evaluated. EC-hepcidin1 showed weak activity against the zoonotic fish pathogen Streptococcus iniae (MIC 100 µg mL-1 and MBC 150 µg mL-1). To study the effect of AMPs in general, and EC-hepcidin1 in particular, a primary cell culture (SC) from the fin tissue of the Caspian Trout (Salmo trutta caspius) was established. The neutral Red method on SC cells revealed that EC-hepcidin1 has no or very low cytotoxic properties. Treatment of cells with either EC-hepcidin1 (150 µg mL-1) or fish pathogen Streptococcus iniae (MOI = 10) and a mixture of both resulted in the up-regulation of gene expression of MHC-UBA, IL-6, and TNFα indicating the modulatory function on inflammatory processes. These findings indicate that EC-hepcidin1 might act as a candidate for modulation of the innate immune system in S. iniae-based infection.