RESUMO
Polyene macrolactams are a special group of natural products with great diversity, unique structural features, and a wide range of biological activities. Herein, a cryptic gene cluster for the biosynthesis of putative macrolactams was disclosed from a sponge-associated bacterium, Streptomyces sp. DSS69, by genome mining. Cloning and heterologous expression of the whole biosynthetic gene cluster led to the discovery of weddellamycin, a polyene macrolactam bearing a 23/5/6 ring skeleton. A negative regulator, WdlO, and two positive regulators, WdlA and WdlB, involved in the regulation of weddellamycin production were unraveled. The fermentation titer of weddellamycin was significantly improved by overexpression of wdlA and wdlB and deletion of wdlO. Notably, weddellamycin showed remarkable antibacterial activity against various Gram-positive bacteria including MRSA, with MIC values of 0.10-0.83 µg/mL, and antifungal activity against Candida albicans, with an MIC value of 3.33 µg/mL. Weddellamycin also displayed cytotoxicity against several cancer cell lines, with IC50 values ranging from 2.07 to 11.50 µM.
Assuntos
Antibacterianos , Lactamas Macrocíclicas , Testes de Sensibilidade Microbiana , Família Multigênica , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Antibacterianos/farmacologia , Antibacterianos/biossíntese , Antibacterianos/química , Humanos , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Polienos/farmacologia , Polienos/isolamento & purificação , Polienos/química , Candida albicans/efeitos dos fármacos , Linhagem Celular Tumoral , Regiões Antárticas , Animais , Poríferos/microbiologia , Antifúngicos/farmacologia , Antifúngicos/química , Antifúngicos/isolamento & purificaçãoRESUMO
Malaymycin (1), a new cyclopentenone-containing tetrahydroquinoline alkaloid, and mccrearamycin E (2), a geldanamycin analogue bearing a rare ring-contracted cyclopentenone moiety, and a C2-symmetric macrodiolide (7) were isolated from Streptomyces malaysiensis SCSIO41397. Their structures including absolute configurations were determined by detailed analyses of NMR and HRMS data and ECD calculations. The occurrence of mccrearamycin E (2) bearing a ring-contracted cyclopentenone is rare in the geldanamycin class. All isolated compounds were evaluated for their cytotoxicities against five cancer cell lines. As a result, compounds 1, 4, 5, and 7 showed cytotoxicity against some or all of the five cancer cell lines with IC50 values ranging from 0.067 to 7.2 µM. In particular, compound 1 inhibited the growth of C42B and H446 cell lines with IC50 values of 67 and 70 nM, respectively. Malaymycin (1) significantly induced cell cycle arrest at the G0/G1 phase in C42B cell lines and caused cell shrinkage and inhibited the expression of the androgen receptor (AR) at both the mRNA and protein levels in a dose-dependent manner. Further examination by qRT-PCR analysis showed that 1 strongly suppressed the expression of AR target genes KLK2 and KLK3 in the C42B and 22RV1 cell lines, which suggested that 1 might be a promising potential lead compound for the development of a treatment for the castration-resistant prostate cancer (CRPC).
Assuntos
Alcaloides/farmacologia , Antagonistas de Receptores de Andrógenos/farmacologia , Benzoquinonas/farmacologia , Ciclopentanos/farmacologia , Lactamas Macrocíclicas/farmacologia , Quinolinas/farmacologia , Streptomyces/química , Alcaloides/isolamento & purificação , Antagonistas de Receptores de Andrógenos/isolamento & purificação , Animais , Benzoquinonas/isolamento & purificação , Linhagem Celular Tumoral , China , Ciclopentanos/isolamento & purificação , Humanos , Lactamas Macrocíclicas/isolamento & purificação , Masculino , Estrutura Molecular , Poríferos/microbiologia , Neoplasias de Próstata Resistentes à Castração , Quinolinas/isolamento & purificação , Receptores AndrogênicosRESUMO
Four polyene macrolactams including the previously reported niizalactam C (4), and three new ones, streptolactams A-C (1-3) with a 26-membered monocyclic, [4,6,20]-fused tricyclic and 11,23-oxygen bridged [14,16]-bicyclic skeletons, respectively, were isolated from the fermentation broth of the deep-sea sediment-derived Streptomyces sp. OUCMDZ-3159. Their structures were determined based on spectroscopic analysis, X-ray diffraction analysis, and chemical methods. The abiotic formation of compounds 2 and 4 from compound 1 were confirmed by a series of chemical reactions under heat and light conditions. Compounds 1 and 3 showed a selective antifungal activity against Candida albicans ATCC 10231.
Assuntos
Antifúngicos/farmacologia , Lactamas Macrocíclicas/farmacologia , Streptomyces/metabolismo , Antifúngicos/isolamento & purificação , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Linhagem Celular Tumoral , Sedimentos Geológicos/microbiologia , Humanos , Lactamas Macrocíclicas/isolamento & purificação , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Mutasynthetic supplementation of the AHBA blocked mutant strain of S. hygroscopicus, the geldanamycin producer, with 21 aromatic and heteroaromatic amino acids provided new nonquinoid geldanamycin derivatives. Large scale (5 L) fermentation provided four new derivatives in sufficient quantity for full structural characterisation. Among these, the first thiophene derivative of reblastatin showed strong antiproliferative activity towards several human cancer cell lines. Additionally, inhibitory effects on human heat shock protein Hsp90α and bacterial heat shock protein from H. pylori HpHtpG were observed, revealing strong displacement properties for labelled ATP and demonstrating that the ATP-binding site of Hsps is the target site for the new geldanamycin derivatives.
Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Proteínas de Choque Térmico/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Benzoquinonas/química , Benzoquinonas/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico/metabolismo , Helicobacter pylori/química , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Estrutura Molecular , Streptomyces/química , Relação Estrutura-AtividadeRESUMO
Four new ansamycins, named divergolides T-W (1-4), along with two known analogs were isolated from the fermentation broth of the mangrove-derived actinomycete Streptomyces sp. KFD18. The structures of the compounds, including the absolute configurations of their stereogenic carbons, were determined by spectroscopic data and single-crystal X-ray diffraction analysis. Compounds 1-4 showed cytotoxic activity against the human gastric cancer cell line SGC-7901, the human leukemic cell line K562, the HeLa cell line, and the human lung carcinoma cell line A549, with 1 being the most active while compounds 5 and 6 were inactive against all the tested cell lines. Compounds 1 and 3 showed very potent and specific cytotoxic activities (IC50 2.8 and 4.7 µM, respectively) against the SGC-7901 cells. Further, the apoptosis-inducing effect of 1 and 3 against SGC-7901 cells was demonstrated by two kinds of staining methods for the first time.
Assuntos
Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Streptomyces/química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Estrutura Molecular , Áreas AlagadasRESUMO
Three new 21-membered macrocyclic benzenoid ansamycins, trienomycins J-L (1-3), together with seven known analogues, trienomycins A-G (4-10), were isolated from liquid culture of the moss soil-derived actinomycete Streptomyces cacaoi subsp. asoensis H2S5. The structures of the new compounds were elucidated by extensive NMR spectroscopic analysis and HRESIMS data. The absolute configurations of trienomycins were established by Marfey's method. Antiproliferative assays showed that compound 1 had the greatest activity against HepG2 cells, with an IC50 value of 0.1 µM. The induction of apoptosis of HepG2 cells by 1 was investigated by flow cytometry and evaluation of nuclear morphology. In addition, all of the compounds inhibited nitric oxide production with IC50 values of 0.02 to 8.3 µM, and compounds 1, 4, and 7 were the most potent inhibitors. These findings will facilitate the development of new antineuroinflammatory agents.
Assuntos
Anti-Inflamatórios/farmacologia , Lactamas Macrocíclicas/isolamento & purificação , Microbiologia do Solo , Streptomyces/metabolismo , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Hep G2 , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Espectroscopia de Ressonância Magnética , Óxido Nítrico/biossínteseRESUMO
Several ansamycins have been reported to inhibit bacterial biofilm formation and accelerate the eradication of developed biofilms, but little is known about the effect of hygrocin C, an ansamycin, on bacterial biofilm formation. Here, hygrocin C was isolated from the marine-derived Streptomyces sp. SCSGAA 0027 and reported for the first time to be capable of inhibiting the biofilm formation of Staphylococcus aureus and Bacillus amyloliquefaciens SCSGAB0082 with the production of anti-microbial lipopeptides from South China Sea gorgonian Subergorgia suberosa at concentrations of less than minimum inhibitory concentrations. Moreover, hygrocin C also promoted the eradication of developed biofilms, affected the biofilm architecture, and lowered the extracellular polymeric matrix formation, cell motility, and surface hydrophobicity in B. amyloliquefaciens, which was in accordance with the inhibition of biofilm formation. Furthermore, transcriptome analysis revealed that hygrocin C altered the transcripts of several genes associated with bacterial chemotaxis and flagellar, two-component system and the synthesis of arginine and histidine, which are important for bacterial biofilm formation. In conclusion, hygrocin C could be used as a potential biofilm inhibitor against S. aureus and B. amyloliquefaciens. But further genetic investigations are needed to provide more details for elucidation of the molecular mechanisms responsible for the effects of hygrocin C on B. amyloliquefaciens biofilm formation.
Assuntos
Antozoários/microbiologia , Bacillus amyloliquefaciens/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Streptomyces/química , Animais , Bacillus amyloliquefaciens/crescimento & desenvolvimento , Proteínas de Bactérias/genética , China , Perfilação da Expressão Gênica , Lactamas Macrocíclicas/isolamento & purificação , Lipopeptídeos/metabolismo , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimentoRESUMO
Mycolic acid-containing bacteria (MACB) are known to activate cryptic natural product biosynthesis in co-cultures with actinobacteria. We cultured Actinosynnema mirum NBRC 14064, a producer of the mono-cyclic polyene macrolactam mirilactam A (6), with the MACB Tsukamurella pulmonis TP-B0596. As a result, three novel compounds (mirilactams C-E, 1-3) were produced in the co-culture conditions. Compounds 1-3 were likely derived from 6 by epoxidation and subsequent spontaneous cyclization. The chemical structures and stereochemistries of 1-3 were determined by spectroscopic analyses (NMR and MS), conformational searches in the optimized potentials for liquid simulations-3 (OPLS3) force field, and calculations of electronic circular dichroism (ECD).
Assuntos
Actinobacteria/química , Actinomycetales/química , Lactamas Macrocíclicas/isolamento & purificação , Ácidos Micólicos/química , Lactamas Macrocíclicas/química , Conformação MolecularRESUMO
Three novel macrocyclic tetralactams, gunnilactam A (1), gunnilactam B (2), and gunnilactam C (3), were isolated from the submerged fermentation broth of Paecilomyces gunnii, an entomogenous fungus identified as the anamorph of Cordyceps gunnii. Their structures were determined using NMR data, HREIMS, and single-crystal X-ray crystallography. Gunnilactam A exhibited selective cytotoxic activity against human prostate cancer C42B cells with an IC50 value of 5.4 µM.
Assuntos
Lactamas Macrocíclicas/isolamento & purificação , Paecilomyces/química , Cordyceps/química , Cristalografia por Raios X , Humanos , Lactamas , Lactamas Macrocíclicas/química , Compostos Macrocíclicos , Estrutura MolecularRESUMO
Two new abscisic acid-type sesquiterpenes (1, 2), and one new ansamycin (3), together with four known ansamycins, namely ansacarbamitocins 4-7, were isolated from the fermentation extract of Amycolatopsis alba DSM 44262. The structures of the new compounds were elucidated to be (E)-3-methyl-5-(2,6,6-trimethyl-3-oxocyclohex-1-enyl)pent-2-enoic acid (1) and (E)-3-methyl-5-(2,6,6-trimethyl-4-oxocyclohex-2-enyl)pent-2-enoic acid (2), and 9-O-methylansacarbamitocin A1 (3), on the basis of comprehensive analysis of spectroscopic data, respectively. The antimicrobial activities were also evaluated for all seven compounds.
Assuntos
Ácido Abscísico/isolamento & purificação , Actinomycetales/química , Lactamas Macrocíclicas/isolamento & purificação , Sesquiterpenos/isolamento & purificação , Ácido Abscísico/química , Ácido Abscísico/farmacologia , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ácidos Graxos Monoinsaturados , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Pseudomonas aeruginosa/efeitos dos fármacos , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , EstereoisomerismoRESUMO
Four cyclopentenone-containing ansamycin polyketides (mccrearamycinsâ A-D), and six new geldanamycins (Gdmsâ B-G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD-23-14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdmâ D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19-hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.
Assuntos
Carvão Mineral/microbiologia , Ciclopentanos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Streptomyces/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclopentanos/química , Ciclopentanos/isolamento & purificação , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Kentucky , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Conformação Molecular , Estereoisomerismo , Streptomyces/metabolismoRESUMO
One new macrolactam derivative, nivelactam (1) and one new polyenoic acid derivative, niveamide (2), along with two other known 20-atom macrolactams (3 and 4) were isolated from the fermentation broth of Streptomyces niveus, which obtained from the forest soil in northeastern China. The structures of 1 and 2 were elucidated on the basis of HRESIMS, IR, and NMR spectroscopic data analyses. Compound 1 was proposed as an intramolecular [4+6]-cycloaddition product of 3 by S. niveus, and displayed moderate cytotoxic activity against a panel of human tumor cell lines in vitro, with IC50 values ranging from 3.76 ± 0.58 to 15.02 ± 2.81 µM.
Assuntos
Reação de Cicloadição , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , Streptomyces/metabolismo , Relação Estrutura-AtividadeRESUMO
Pseudoverticin B (1), a novel naturally occurring geldanamycin analog with cell cycle inhibitory activity, was isolated from the fermentation broth of Streptomyces pseudoverticillus YN17707, together with the known ansamycin antibiotic, hydroquinone geldanamycin (2), through bioassay-guided fractionation procedures. The structure of compound 1 was elucidated by spectroscopic methods, being characterized by an ansa bridge, same as that in geldanamycin and a novel hydroquinone-derived moiety. Compounds 1 and 2 arrested the cell cycle of tsFT210 cells at the G0/G1 phase with the minimum inhibitory concentration values of 10.1 and 20.2 µmolL(-1), respectively.
Assuntos
Benzoquinonas/isolamento & purificação , Benzoquinonas/farmacologia , Lactamas Macrocíclicas/isolamento & purificação , Lactamas Macrocíclicas/farmacologia , Antibacterianos/farmacologia , Benzoquinonas/química , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular , Lactamas Macrocíclicas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Streptomyces/químicaRESUMO
Thiazinogeldanamycin (2) was identified from Streptomyces hygroscopicus 17997 at the late stage of the fermentation. The pH was firstly proposed as an important factor in the biosynthesis of it. It was verified that 2 was produced by direct chemical reactions between geldanamycin (1, GDM) and cysteine or aminoethanethiol hydrochloride at pH > 7 in vitro. The proposed synthesis pathway for compound 2 was also discussed. Eleven new C-19-modified GDM derivatives, including five stable hydroquinone form derivatives, were synthesized, most of which exhibited desirable properties such as lower cytotoxicity, increased water solubility, and potent antitumor activity. Especially, compounds 5 and 8 showed antitumor activities against HepG2 cell with IC50 values of 2.97-6.61 µM, lower cytotoxicity and at least 15-fold higher water solubility compared with 1 in pH 7.0 phosphate buffer.
Assuntos
Antineoplásicos , Benzoquinonas , Hidroquinonas/síntese química , Lactamas Macrocíclicas , Streptomyces/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/isolamento & purificação , Benzoquinonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Hidroquinonas/química , Concentração Inibidora 50 , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Lactamas Macrocíclicas/farmacologia , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , SolubilidadeRESUMO
Two new polycyclic tetramate macrolactams, lysobacteramides A (1) and B (2), together with HSAF (heat-stable antifungal factor, 3), 3-dehydroxy HSAF (4), and alteramide A (5) were isolated from a culture of Lysobacter enzymogenes C3 in nutrient yeast glycerol medium. Their structures were determined by MS and extensive NMR analysis. The absolute configurations of 1-5 were assigned by theoretical calculations of their ECD spectra. Although HSAF and analogues were reported from several microorganisms, their absolute configurations had not been established. The isolation and the absolute configurations of these compounds revealed new insights into the biosynthetic mechanism for formation of the polycycles. Compounds 1-4 exhibited cytotoxic activity against human carcinoma A549, HepG2, and MCF-7 cells with IC50 values ranging from 0.26 to 10.3 µM. Compounds 2 and 3 showed antifungal activity against Fusarium verticillioides with IC50 value of 47.9 and 6.90 µg/mL, respectively.
Assuntos
Lactamas Macrocíclicas/isolamento & purificação , Lactamas Macrocíclicas/farmacologia , Lysobacter/química , Antifúngicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Fusarium/efeitos dos fármacos , Células Hep G2 , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/química , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Policetídeo Sintases/metabolismoRESUMO
A terrestrial bacterium, Streptomyces sp. NZ-6, produced niizalactams A-C (1-3), unprecedented di- and tricyclic macrolactams, by coculturing with the mycolic acid-containing bacterium Tsukamurella pulmonis TP-B0596. Their complete structures, including absolute configurations, were elucidated on the basis of spectroscopic data and chemical derivatization. Their unique skeletons are proposed to be biosynthesized from a common 26-membered macrolactam intermediate by SN2 cyclization or an intramolecular Diels-Alder reaction.
Assuntos
Lactamas Macrocíclicas/isolamento & purificação , Streptomyces/química , Animais , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Leucemia P388 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ácidos Micólicos/química , Ressonância Magnética Nuclear Biomolecular , Saccharomyces cerevisiae/efeitos dos fármacosRESUMO
One new bicyclic lactam, cladosporilactam A (1), and six known 12-membered macrolides (2-7) were isolated from a gorgonian-derived Cladosporium sp. fungus collected from the South China Sea. Their complete structural assignments were elucidated by comprehensive spectroscopic investigation. Quantum chemistry calculations were used in support of the structural determination of 1. The absolute configuration of 1 was determined by calculation of its optical rotation. Cladosporilactam A (1) was the first example of 7-oxabicyclic[6.3.0]lactam obtained from a natural source. Compound 1 exhibited promising cytotoxic activity against cervical cancer HeLa cell line with an IC50 value of 0.76 µM.
Assuntos
Antineoplásicos/isolamento & purificação , Organismos Aquáticos/química , Ascomicetos/química , Compostos Bicíclicos Heterocíclicos com Pontes/isolamento & purificação , Lactamas Macrocíclicas/isolamento & purificação , Lactamas/isolamento & purificação , Macrolídeos/isolamento & purificação , Animais , Antozoários/microbiologia , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células HeLa/efeitos dos fármacos , Humanos , Lactamas/farmacologia , Lactamas Macrocíclicas/farmacologia , Macrolídeos/farmacologia , Espectroscopia de Ressonância MagnéticaRESUMO
Three new macrolactams, heronamides D-F (1-3), were isolated from the deep-sea-derived Streptomyces sp. SCSIO 03032 upon changing cultivation conditions. The planar structures of heronamides D-F (1-3) were elucidated by extensive MS and NMR spectroscopic analyses and comparisons with the closely related heronamides A-C. The relative configurations of 1-3 were deduced by detailed analysis of (3)JHH values and NOESY data. The absolute configurations of 1 and 2 were determined by chemical modifications and application of the modified Mosher's method. None of the compounds exhibited obvious antimicrobial or cytotoxic activities.
Assuntos
Lactamas Macrocíclicas/isolamento & purificação , Polilisina/isolamento & purificação , Streptomyces/química , Anti-Infecciosos , Bacillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oceanos e Mares , Polilisina/química , Polilisina/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
A new actinomycete strain Micromonospora sp. K310 was isolated from Ghanaian mangrove river sediment. Spectroscopy-guided fractionation led to the isolation of two new compounds from the fermentation culture. One of the compounds is butremycin (2) which is the (3-hydroxyl) derivative of the known Streptomyces metabolite ikarugamycin (1) and the other compound is a protonated aromatic tautomer of 5'-methylthioinosine (MTI) (3). Both new compounds were characterized by 1D, 2D NMR and MS data. Butremycin (2) displayed weak antibacterial activity against Gram-positive S. aureus ATCC 25923, the Gram-negative E. coli ATCC 25922 and a panel of clinical isolates of methicillin-resistant S. aureus (MRSA) strains while 3 did not show any antibacterial activity against these microbes.
Assuntos
Antibacterianos/farmacologia , Lactamas Macrocíclicas/farmacologia , Metiltioinosina/análogos & derivados , Micromonospora/química , Antibacterianos/química , Antibacterianos/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Fermentação , Sedimentos Geológicos/microbiologia , Gana , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/isolamento & purificação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Metiltioinosina/química , Metiltioinosina/isolamento & purificação , Metiltioinosina/farmacologia , Testes de Sensibilidade Microbiana , Rios/microbiologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
A new polycyclic tetramate macrolactam designated allostreptamide (1), together with four known congeners, were isolated from the culture extract of Allostreptomyces RD068384. The planar structure of the new compound was elucidated through interpretation of NMR and MS data. The absolute configuration was determined through ROESY and ECD analyses. The isolated compounds revealed antifungal potential against fourteen Candida albicans isolates with minimum inhibitory concentrations (MICs) ranging from 64 to 2048 µg ml-1. Compound 3 showed antibiofilm action and considerably reduced the viability of five isolates (36%) in the formed biofilm. The qRT-PCR revealed that 3 downregulated the BCR1, PLB2, ALS1, and SAP5 biofilm related gene expression. Therefore, 3 could be a promising antifungal therapy for C. albicans infections.