RESUMO
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.
Assuntos
Anti-Inflamatórios , Líquens , NF-kappa B , Fenazinas , Streptomyces , Peixe-Zebra , Animais , Streptomyces/química , Líquens/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Fenazinas/farmacologia , Fenazinas/química , Estrutura Molecular , NF-kappa B/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Microglia/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Antimicrobial resistance is expected to increase mortality rates by up to several million deaths per year by 2050 without new treatment options at hand. Recently, we characterized the pharmacokinetic (PK) and pharmacodynamic properties of two atypical tetracyclines, chelocardin (CHD) and amidochelocardin (CDCHD) that exhibit no cross-resistance with clinically used antibacterials. Both compounds were preferentially renally cleared and demonstrated pronounced effects in an ascending urinary tract infection model against E. coli. Renal drug transporters are known to influence clearance into the urine. In particular, inhibition of apical transporters in renal tubular epithelial cells can lead to intracellular accumulation and potential cell toxicity, whereas inhibition of basolateral transporters can cause a higher systemic exposure. Here, selected murine and human organic cation (Oct), organic anion (Oat), and efflux transporters were studied to elucidate interactions with CHD and CDCHD underlying their PK behavior. CHD exhibited stronger inhibitory effects on mOat1 and mOat3 and their human homologues hOAT1 and hOAT3 compared to CDCHD. While CHD was a substrate of mOat3 and mOct1, CDCHD was not. By contrast, no inhibitory effect was observed on Octs. CDCHD rather appeared to foster enhanced substrate transport on mOct1. CHD and CDCHD inhibited the efflux transporter hMRP2 on the apical side. In summary, the substrate nature of CHD in conjunction with its autoinhibition toward mOat3 rationalizes the distinct urine concentration profile compared to CDCHD that was previously observed in vivo. Further studies are needed to investigate the accumulation in renal tubular cells and the nephrotoxicity risk.
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Chemical investigation of the solid-state rice culture of the endangered European polypore Fomitiporia hartigii (Hymenochaetaceae) afforded a previously undescribed protoilludene derivative (1) in addition to six known compounds (2-7). Chemical structures of the isolated compounds were established based on HR-ESI-MS, comprehensive 1D/2D NMR spectroscopic analyses, and comparisons with the literature. All isolated compounds were assessed for their cytotoxic and antimicrobial activities. Among the tested compounds, hymeglusin (3) revealed potent cytotoxic activity against all tested cell lines with IC50 values between 0.3 and 6.8 µM. Compound 3 and fusaridioic acid A (4) revealed weak to moderate antimicrobial activities with its most potent effect against Candida albicans (minimum inhibitory concentration of 4.2 µg/mL).
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In the course of our ongoing research targeting the identification of potential biocontrol agents from entomopathogenic fungi (EPF), we explored a solid-state rice fungal extract of Blackwellomyces roseostromatus BCC56290 derived from infected lepidopteran larvae. Chemical and biological prospections afforded four unprecedentedly reported natural products differentiated into a dimeric naphthopyran bioxanthracene ES-242 derivative (1) and three cyclodepsipeptides (2-4) in addition to two known cyclodepsipeptides, cardinalisamides B (5) and C (6). Chemical structures of the isolated compounds were elucidated through comprehensive 1D/2D NMR and HR-ESI-MS data together with comparisons to the reported literature. The absolute configuration of the isolated cyclodepsipeptides was determined using Marfey's method. All isolated compounds were assessed for their antimicrobial, cytotoxic, and nematicidal activities with some compounds revealing significant activities.
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The debates over the requirement of the International Code of Nomenclature for algae, fungi, and plants (ICNafp) for a viable specimen to represent the name-bearing type material for a species or infraspecific taxon have a long history. Taxonomy of fungi commonly studied as living cultures exemplified by yeasts and moulds, strongly depend on viable reference material. The availability of viable cultures is also particularly useful for several groups of filamentous and dimorphic fungi. While the preservation of metabolically inactive cultures is permitted and recommended by the ICNafp, there is room for improvement. Below, we review the history and current status of cultures as the name-bearing type material under the Code. We also present a roadmap with tasks to be achieved in order to establish a stable nomenclatural system that properly manages taxa typified by viable specimens. Furthermore, we propose setting up rules and defining the nomenclatural status of ex-type cultures under Chapter F, the section of the ICNafp that includes provisions specific to names of fungi.
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A chemical investigation of Laburnicola nematophila, isolated from cysts of the plant parasitic nematode Heterodera filipjevi, affored three dactylfungin derivatives (1-3) and three tetralone congeners (4-6). Dactylfungin C (1), laburnicolin (4), and laburnicolenone (5) are previously undescribed natural products. Chemical structures of the isolated compounds were determined based on 1D and 2D NMR spectroscopic analyses together with HR-ESI-MS spectrometry and comparison with data reported in the literature. The relative configurations of compounds 1, 2, and 4-6 were determined based on their ROESY data and analysis of their coupling constants (J values). The absolute configurations of 4-6 were determined through the comparison of their measured and calculated TDDFT-ECD spectra. Compounds 1-3 were active against azole-resistant Aspergillus fumigatus.
Assuntos
Tetralonas , Animais , Estrutura Molecular , Tetralonas/farmacologia , Tetralonas/química , Antifúngicos/farmacologia , Antifúngicos/química , Testes de Sensibilidade Microbiana , Tylenchoidea/efeitos dos fármacosRESUMO
A chemical and biological exploration of the European polypore Dentipellis fragilis afforded two previously undescribed natural products (1 and 2), together with three known derivatives (3-5). Chemical structures of the isolated compounds were confirmed through 1D/2D NMR spectroscopic analyses, mass spectrometry, and by comparison with the reported literature. The relative and absolute configurations of 1 were determined according to the ROESY spectrum and time-dependent density functional theory electronic circular dichroism (TDDFT-ECD), respectively. Furthermore, the absolute configuration of dentipellinol (3) was revisited and revealed to be of (R) configuration. All the isolated compounds were assessed for their cytotoxic and antimicrobial activities, with some being revealed to have weak to moderate antimicrobial activity, particularly against Gram-positive bacteria.
Assuntos
Testes de Sensibilidade Microbiana , Humanos , Estrutura Molecular , Basidiomycota/química , Espectroscopia de Ressonância Magnética , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Dicroísmo Circular , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Bactérias Gram-Positivas/efeitos dos fármacos , Linhagem Celular TumoralRESUMO
Nematode-associated fungi revealed the potential to produce a broad spectrum of chemical scaffolds. In this study, a mycelial extract of Laburnicola nematophila, a fungal strain derived from the cereal cyst nematode Heterodera filipjevi, was chemically explored and afforded six unprecedentedly reported acylic N-acetyl oligopeptides, laburnicotides A-F (1-6). Structure elucidation of the isolated compounds was established based on comprehensive 1D and 2D NMR spectroscopic analyses together with the acquired HR-ESI-MS spectrometric data. The absolute configuration of amino acid residues in 1-6 was established by performing advanced Marfey's derivatization method. All isolated compounds were assessed for their cytotoxic, antimicrobial, antiviral, and nematicidal activities with no potential activity observed.
RESUMO
A chemical investigation of a methanol extract derived from a solid-state rice culture of the nematode-cyst associated fungus Laburnicola nematophila K01 led to the isolation and characterization of a previously undescribed penillic acid analogue named laburnicolamine (1). The chemical structure was elucidated through comprehensive 1D and 2Dâ NMR spectroscopic analyses in methanol-d4 and DMSO-d6, alongside with HR-ESI-MS spectrometry. The absolute configuration of 1 was concluded through the electronic circular dichroism (ECD) and time-dependent density functional theory-ECD (TDDFT-ECD) computations compared to its acquired spectrum. Biological assays revealed that compound 1 exhibited no significant cytotoxic, antimicrobial, or nematicidal activity.
Assuntos
Testes de Sensibilidade Microbiana , Animais , Humanos , Teoria da Densidade Funcional , Nematoides/efeitos dos fármacos , Conformação Molecular , Estrutura Molecular , Hypocreales/químicaRESUMO
During the course of our ongoing studies on the secondary metabolism of cultures of Basidiomycota, a new meroterpenoid named 10, 15-dihydroxydihydromelleolide (1) was isolated along with the known armillaridin (2) and arnamiol (3) from cultures of the rare saprotrophic species, Desarmillaria ectypa. These are the first secondary metabolites that were ever isolated from the latter species. A concurrently studied strain of the common pathogenic A. mellea yielded other melleolides, with 5'-O-methylmelledonal (4), melledonal C (5), 10 α-hydroxydihydromelleolide (6) and melledonal (7). The chemical structures were elucidated using 1D and 2D NMR spectroscopy and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). All compounds were studied for their antimicrobial and cytotoxic effects against a panel of microbes and mammalian cell lines, and the results are also reported.
Assuntos
Armillaria , Testes de Sensibilidade Microbiana , Metabolismo Secundário , Armillaria/química , Armillaria/metabolismo , Humanos , Basidiomycota/química , Basidiomycota/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificação , Antifúngicos/metabolismo , Estrutura Molecular , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismoRESUMO
Two unprecedented isomeric secondary metabolites named vibralactones Z5 (1a) and Z6 (1b), in addition to eleven known compounds (2-12), were isolated from solid-state rice culture medium of Bondarzewia mesenterica (Bondarzewiaceae). Chemical structures of the isolated compounds were established via spectral analyses. The new lactone derivatives were weakly active against Staphylococcus aureus without any significant cytotoxicity, while the molecules containing an aldehyde functionality showed significant antimicrobial and cytotoxic effects. For instance, erinacine P (7) and (+)-isovelleral (8) and erinacine P (7) were cytotoxic against all tested cell lines at IC50 values in the ranges of 3.5-14.2 and 2.8-30.2 µM, respectively. In addition, they revealed moderate antimicrobial activity with the lowest minimum inhibitory concentration (MIC) values recorded against Mucor hiemalis (8.3 µg/mL), Pichia anomala, and Rhodotorula glutinis at 16.6 µg/mL.
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The continued emergence of Neisseria gonorrhoeae strains that express resistance to multiple antibiotics, including the last drug for empiric monotherapy (ceftriaxone), necessitates the development of new treatment options to cure gonorrheal infections. Toward this goal, we recently reported that corallopyronin A (CorA), which targets the switch region of the ß' subunit (RpoC) of bacterial DNA-dependent RNA polymerase (RNAP), has potent anti-gonococcal activity against a panel of multidrug-resistant clinical strains. Moreover, in that study, CorA could eliminate gonococcal infection of primary human epithelial cells and gonococci in a biofilm state. To determine if N. gonorrhoeae could develop high-level resistance to CorA in a single step, we sought to isolate spontaneous mutants expressing any CorA resistance phenotypes. However, no single-step mutants with high-level CorA resistance were isolated. High-level CorA resistance could only be achieved in this study through a multi-step pathway involving over-expression of the MtrCDE drug efflux pump and single amino acid changes in the ß and ß' subunits (RpoB and RpoC, respectively) of RNAP. Molecular modeling of RpoB and RpoC interacting with CorA was used to deduce how the amino acid changes in RpoB and RpoC could influence gonococcal resistance to CorA. Bioinformatic analyses of whole genome sequences of clinical gonococcal isolates indicated that the CorA resistance determining mutations in RpoB/C, identified herein, are very rare (≤ 0.0029%), suggesting that the proposed pathway for resistance is predictive of how this phenotype could potentially evolve if CorA is used therapeutically to treat gonorrhea in the future. IMPORTANCE: The continued emergence of multi-antibiotic-resistant strains of Neisseria gonorrhoeae necessitates the development of new antibiotics that are effective against this human pathogen. We previously described that the RNA polymerase-targeting antibiotic corallopyronin A (CorA) has potent activity against a large collection of clinical strains that express different antibiotic resistance phenotypes including when such gonococci are in a biofilm state. Herein, we tested whether a CorA-sensitive gonococcal strain could develop spontaneous resistance. Our finding that CorA resistance could only be achieved by a multi-step process involving over-expression of the MtrCDE efflux pump and single amino acid changes in RpoB and RpoC suggests that such resistance may be difficult for gonococci to evolve if this antibiotic is used in the future to treat gonorrheal infections that are refractory to cure by other antibiotics.
Assuntos
Antibacterianos , Proteínas de Bactérias , RNA Polimerases Dirigidas por DNA , Gonorreia , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/enzimologia , RNA Polimerases Dirigidas por DNA/genética , RNA Polimerases Dirigidas por DNA/metabolismo , Antibacterianos/farmacologia , Humanos , Gonorreia/microbiologia , Gonorreia/tratamento farmacológico , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/genética , Mutação , Farmacorresistência Bacteriana Múltipla/genética , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , LactonasRESUMO
Plants are associated with a large diversity of microbes, and these complex plant-associated microbial communities are critical for plant health. Welsh onion (Allium fistulosum L.) is one of the key and oldest vegetable crops cultivated in Taiwan. The leaf of the Welsh onion is one of the famous spices in Taiwanese cuisine, thus, it is crucial to control foliar diseases. In recent years, Welsh onion cultivation in Taiwan has been severely threatened by the occurrence of leaf blight disease, greatly affecting their yield and quality. However, the overall picture of microbiota associated with the Welsh onion plant is still not clear as most of the recent etiological investigations were heavily based on the isolation of microorganisms from diseased plants. Therefore, studying the diversity of fungal communities associated with the leaf blight symptoms of Welsh onion may provide information regarding key taxa possibly involved in the disease. Therefore, this investigation was mainly designed to understand the major fungal communities associated with leaf blight to identify key taxa potentially involved in the disease and further evaluate any shifts in both phyllosphere and rhizosphere mycobiome assembly due to foliar pathogen infection by amplicon sequencing targeting the Internal Transcribed Spacer (ITS) 1 region of the rRNA. The alpha and beta-diversity analyses were used to compare the fungal communities and significant fungal groups were recognized based on linear discriminant analyses. Based on the results of relative abundance data and co-occurrence networks in symptomatic plants we revealed that the leaf blight of Welsh onion in Sanxing, is a disease complex mainly involving Stemphylium and Colletotrichum taxa. In addition, genera such as Aspergillus, Athelia and Colletotrichum were abundantly found associated with the symptomatic rhizosphere. Alpha-diversity in some fields indicated a significant increase in species richness in the symptomatic phyllosphere compared to the asymptomatic phyllosphere. These results will broaden our knowledge of pathogens of Welsh onion associated with leaf blight symptoms and will assist in developing effective disease management strategies to control the progress of the disease.
RESUMO
The synthesis of a novel disorazole C1 analogue is described, and its biological activity as a cytotoxic compound is reported. Based on our convergent and flexible route to the disorazole core, we wish to report a robust strategy to synthesize a non-symmetrical disorazole in which we couple one half of the molecule containing the naturally occurring oxazole heterocycle and the second half of the disorazole macrocycle containing a thiazole heterocycle. This resulted in a very unusual non-symmetrical disorazole C1 analogue containing two different heterocycles, and its biological activity was studied. This provided exciting information about SAR (structure-activity-relationship) for this highly potent class of antitumor compounds.
Assuntos
Antineoplásicos , Macrolídeos , Relação Estrutura-AtividadeRESUMO
Chemical exploration for two isolates of the recently described ascomycete species Polyphilus sieberi, derived from the eggs of the plant parasitic nematode Heterodera filipjevi, afforded the identification of many compounds that belong to various metabolite families: two previously undescribed chlorinated cyclotetrapeptides, omnipolyphilins A (1) and B (2), one new pyranonaphthoquinone, ventiloquinone P (3), a 6,6'-binaphto-α-pyranone dimer, talaroderxine D (4) in addition to nine known metabolites (5-13) were isolated from this biocontrol candidate. All isolated compounds were characterized by comprehensive 1D, 2D NMR, and HR-ESI-MS analyses. The absolute configurations of the cyclotetrapeptides were determined by a combination of advanced Marfey's method, ROE correlation aided by conformational analysis, and TDDFT-ECD calculations, while ECD calculations, Mosher's method, and experimental ECD spectra were used for ventiloquinone P (3) and talaroderxine D (4). Among the isolated compounds, talaroderxine D (4) showed potent antimicrobial activities against Bacillus subtilis and Staphylococcus aureus with MIC values of 2.1 and 8.3 µg mL-1, respectively. Additionally, promising inhibitory effects on talaroderxine D (4) against the formation of S. aureus biofilms were observed up to a concentration of 0.25 µg mL-1. Moreover, ophiocordylongiiside A (10) showed activity against the free-living nematode Caenorhabditis elegans.
Assuntos
Ascomicetos , Tylenchoidea , Humanos , Animais , Staphylococcus aureus , Bacillus subtilis , Estrutura MolecularRESUMO
Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.
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Three novel derivatives of microporenic acid, microporenic acids H-J, were identified from submerged cultures of a Lentinus species obtained from a basidiome collected during a field trip in the tropical rainforest in Western Kenya. Their structures were elucidated via HR-ESIMS spectra and 1D/2D NMR spectroscopic analyses, as well as by comparison with known derivatives. Applying biofilm assays based on crystal violet staining and confocal microscopy, two of these compounds, microporenic acids H and I, demonstrated the ability to inhibit biofilm formation of the opportunistic pathogen Staphylococcus aureus. Thereby, they were effective in a concentration range that did not affect planktonic growth. Additionally, microporenic acid I enhanced the anti-biofilm activity of the antibiotics vancomycin and gentamicin when used in combination. This opens up possibilities for the use of these compounds in combination therapy to prevent the formation of S. aureus biofilms.
Assuntos
Antibacterianos , Biofilmes , Lentinula , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/isolamento & purificação , Estrutura Molecular , Lentinula/química , Quênia , Testes de Sensibilidade Microbiana , Vancomicina/farmacologia , Gentamicinas/farmacologiaAssuntos
Antibacterianos , Chlamydia trachomatis , RNA Polimerases Dirigidas por DNA , Chlamydia trachomatis/efeitos dos fármacos , Chlamydia trachomatis/genética , RNA Polimerases Dirigidas por DNA/genética , Antibacterianos/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Mutação , Inibidores Enzimáticos/farmacologiaRESUMO
The natural product chlorotonil displays high potency against multidrug-resistant Gram-positive bacteria and Plasmodium falciparum. Yet, its scaffold is characterized by low solubility and oral bioavailability, but progress was recently made to enhance these properties. Applying late-stage functionalization, we aimed to further optimize the molecule. Previously unknown reactions including a sulfur-mediated dehalogenation were revealed. Dehalogenil, the product of this reaction, was identified as the most promising compound so far, as this new derivative displayed improved solubility and in vivo efficacy while retaining excellent antimicrobial activity. We confirmed superb activity against multidrug-resistant clinical isolates of Staphylococcus aureus and Enterococcus spp. and mature transmission stages of Plasmodium falciparum. We also demonstrated favorable in vivo toxicity, pharmacokinetics and efficacy in infection models with S. aureus. Taken together, these results identify dehalogenil as an advanced lead molecule.