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1.
Angew Chem Int Ed Engl ; 59(14): 5607-5610, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-31880848

RESUMO

Butenolides are well-known signaling molecules in Gram-positive bacteria. Here, we describe a novel class of butenolides isolated from a Gram-negative Pseudomonas strain, the styrolides. Structure elucidation was aided by the total synthesis of styrolide A. Transposon mutagenesis enabled us to identify the styrolide biosynthetic gene cluster, and by using a homology search, we discovered the related and previously unknown acaterin biosynthetic gene cluster in another Pseudomonas species. Mutagenesis, heterologous expression, and identification of key shunt and intermediate products were crucial to propose a biosynthetic pathway for both Pseudomonas-derived butenolides. Comparative transcriptomics suggests a link between styrolide formation and the regulatory networks of the bacterium.


Assuntos
4-Butirolactona/análogos & derivados , Pseudomonas/química , 4-Butirolactona/biossíntese , 4-Butirolactona/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Elementos de DNA Transponíveis/genética , Família Multigênica , Mutagênese , Pseudomonas/genética , Pseudomonas/isolamento & purificação , Microbiologia do Solo
2.
Artigo em Inglês | MEDLINE | ID: mdl-29358295

RESUMO

Scrub typhus is a potentially lethal infection caused by the obligate intracellular bacterium Orientia tsutsugamushi Reports on the emergence of doxycycline-resistant strains highlight the urgent need to develop novel antiinfectives against scrub typhus. Corallopyronin A (CorA) is a novel α-pyrone compound synthesized by the myxobacterium Corallococcus coralloides that was characterized as a noncompetitive inhibitor of the switch region of the bacterial RNA polymerase (RNAP). We investigated the antimicrobial action of CorA against the human-pathogenic Karp strain of O. tsutsugamushiin vitro and in vivo The MIC of CorA against O. tsutsugamushi was remarkably low (0.0078 µg/ml), 16-fold lower than that against Rickettsia typhi In the lethal intraperitoneal O. tsutsugamushi mouse infection model, a minimum daily dose of 100 µg CorA protected 100% of infected mice. Two days of treatment were sufficient to confer protection. In contrast to BALB/c mice, SCID mice succumbed to the infection despite treatment with CorA or tetracycline, suggesting that antimicrobial treatment required synergistic action of the adaptive immune response. Similar to tetracycline, CorA did not prevent latent infection of O. tsutsugamushiin vivo However, latency was not caused by acquisition of antimicrobial resistance, since O. tsutsugamushi reisolated from latently infected BALB/c mice remained fully susceptible to CorA. No mutations were found in the CorA-binding regions of the ß and ß' RNAP subunit genes rpoB and rpoC Inhibition of the RNAP switch region of O. tsutsugamushi by CorA is therefore a novel and highly potent target for antimicrobial therapy for scrub typhus.


Assuntos
Antibacterianos/uso terapêutico , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Lactonas/uso terapêutico , Orientia tsutsugamushi/patogenicidade , Tifo por Ácaros/tratamento farmacológico , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Myxococcales/efeitos dos fármacos , Myxococcales/patogenicidade , Orientia tsutsugamushi/efeitos dos fármacos , Rickettsia typhi/efeitos dos fármacos , Rickettsia typhi/patogenicidade , Tifo por Ácaros/microbiologia
3.
Bioorg Med Chem ; 25(22): 6088-6097, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28893599

RESUMO

Illumina 16S rRNA gene sequencing was used to profile the associated bacterial community of the marine hydroid Hydractinia echinata, a long-standing model system in developmental biology. 56 associated bacteria were isolated and evaluated for their antimicrobial activity. Three strains were selected for further in-depth chemical analysis leading to the identification of 17 natural products. Several γ-Proteobacteria were found to induce settlement of the motile larvae, but only six isolates induced the metamorphosis to the primary polyp stage within 24h. Our study paves the way to better understand how bacterial partners contribute to protection, homeostasis and propagation of the hydroid polyp.


Assuntos
Bactérias/genética , Produtos Biológicos/química , Gammaproteobacteria/metabolismo , Hidrozoários/microbiologia , Animais , Bactérias/classificação , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Cromatografia Líquida de Alta Pressão , Gammaproteobacteria/classificação , Gammaproteobacteria/genética , Sequenciamento de Nucleotídeos em Larga Escala , Hidrozoários/crescimento & desenvolvimento , Larva/microbiologia , Espectrometria de Massas , Metamorfose Biológica/efeitos dos fármacos , Filogenia , RNA Ribossômico 16S/química , RNA Ribossômico 16S/classificação , RNA Ribossômico 16S/metabolismo , Análise de Sequência de DNA
4.
Angew Chem Int Ed Engl ; 55(39): 11955-9, 2016 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-27559694

RESUMO

The regioselective functionalization of non-activated carbon atoms such as aliphatic halogenation is a major synthetic challenge. A novel multifunctional enzyme catalyzing the geminal dichlorination of a methyl group was discovered in Aspergillus oryzae (Koji mold), an important fungus that is widely used for Asian food fermentation. A biosynthetic pathway encoded on two different chromosomes yields mono- and dichlorinated polyketides (diaporthin derivatives), including the cytotoxic dichlorodiaporthin as the main product. Bioinformatic analyses and functional genetics revealed an unprecedented hybrid enzyme (AoiQ) with two functional domains, one for halogenation and one for O-methylation. AoiQ was successfully reconstituted in vivo and in vitro, unequivocally showing that this FADH2 -dependent enzyme is uniquely capable of the stepwise gem-dichlorination of a non-activated carbon atom on a freestanding substrate. Genome mining indicated that related hybrid enzymes are encoded in cryptic gene clusters in numerous ecologically relevant fungi.


Assuntos
Aspergillus oryzae/enzimologia , Fenóis/metabolismo , Aspergillus oryzae/genética , Aspergillus oryzae/metabolismo , Vias Biossintéticas , Fermentação , Genes Fúngicos , Halogenação , Metilação , Fenóis/química , Policetídeos/química , Policetídeos/metabolismo , Estereoisomerismo
5.
Appl Microbiol Biotechnol ; 88(1): 241-9, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20596706

RESUMO

Trisporic acid, its precursors and derivatives are used within zygomycete fungi as communication signals and sexual regulators, and also influence the production rate of the parent compound, beta-carotene. Cultivation parameters during growth and the trisporoid production phase of Blakeslea trispora were studied in two-step shake flask cultures and up-scaled fermentations. Comparison of various fermentation protocols allowed the definition of parameters governing trisporoid production. Highest yields were obtained when the initial growth phase allowed for both rapid growth and fast exhaustion of nitrogen and phosporous sources. Onset of trisporoid production is accompanied by a pH drop in the medium and triggered by nutrient limitation, nitrogen depletion being the most important factor. Supplementation of cultures with carbon at low concentration after onset of trisporoid production led to prolonged growth and higher final product accumulation. B. trispora produces trisporoids in two major series, B and C. During a first peak in trisporic acid accumulation, production of trisporic acid B exceeds that of trisporic acid C, which later accumulates at the expense of the trisporic acid B, indicating a variable regulation of the ratio between these metabolites. These data are valuable for tailoring production systems for enrichment of specific intermediates of this complex signal family.


Assuntos
Ácidos Graxos Insaturados/metabolismo , Mucorales/metabolismo , Carbono/metabolismo , Meios de Cultura/química , Ácidos Graxos Insaturados/química , Fermentação , Concentração de Íons de Hidrogênio , Mucorales/crescimento & desenvolvimento , Nitrogênio/metabolismo , Fósforo/metabolismo , beta Caroteno/metabolismo
6.
J Antibiot (Tokyo) ; 63(7): 359-63, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20551984

RESUMO

A new bafilomycin-type macrolide, named hygrobafilomycin (6), was isolated by a bioassay-guided selection and fractionation from a terrestrial actinomycete, Streptomyces varsoviensis, along with three known derivatives, bafilomycin D (3), C1 (4) and C2 (5). The structure of hygrobafilomycin was fully established by MS and NMR analyses, revealing a hygrolidin-bafilomycin hybrid with an unusual monoalkylmaleic anhydride moiety. Hygrobafilomycin (6) shows strong antifungal, antiproliferative and cytotoxic activities. In a panel of 40 tumor cell lines, compound 6 shows high cytotoxic potency (mean IC(50)=5.3 n).


Assuntos
Antibióticos Antineoplásicos/isolamento & purificação , Antibióticos Antineoplásicos/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Macrolídeos/isolamento & purificação , Macrolídeos/farmacologia , Maleatos/isolamento & purificação , Maleatos/farmacologia , Streptomyces/química , Antibióticos Antineoplásicos/química , Antifúngicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macrolídeos/química , Macrolídeos/metabolismo , Espectroscopia de Ressonância Magnética , Maleatos/química , Maleatos/metabolismo , Espectrometria de Massas , Estrutura Molecular , Streptomyces/metabolismo
7.
Org Biomol Chem ; 6(19): 3601-5, 2008 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-19082162

RESUMO

Gilvocarcin-type polyketide glycosides represent some of the most powerful antitumor therapeutics. Bioactivity-guided fractionation of a culture extract of Streptomyces polyformus sp. nov. (YIM 33176) yielded the known gilvocarcin V (2) and a novel related compound, polycarcin V (1). Structure elucidation by NMR and chemical derivatization revealed that the congener (1) features a C-glycosidically linked alpha-L-rhamnopyranosyl moiety in lieu of the D-fucofuranose. The concomitant production of two distinct furanosyl and pyranosyl C-glycosides that share the same aglycone is unprecedented in bacteria. A conversion of both isoforms via a quinone methide intermediate can be ruled out, thus pointing to two individual C-glycosylation pathways. Cytotoxicity profiling of polycarcin V in a panel of 37 tumor cell lines indicated significant antitumoral activity with a pronounced selectivity for non-small-cell lung cancer, breast cancer and melanoma cells. As the antiproliferative fingerprint is identical to that of actinomycin D, the known DNA interaction of gilvocarcins was established as a general principle of antitumorigenic activity.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Descoberta de Drogas , Glicosídeos/biossíntese , Glicosídeos/farmacologia , Streptomyces/metabolismo , Antineoplásicos/análise , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cumarínicos/análise , Cumarínicos/química , Glicosídeos/análise , Glicosídeos/química , Humanos
8.
Chembiochem ; 9(18): 3004-12, 2008 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-19035372

RESUMO

The fungal phylum zygomycota uses trisporic acids (TSAs), a family of apocarotenoids, during sexual reproduction to synchronize and control activity between the mycelial hyphae of opposite mating types. Separate as well as mixed cultures of Blakeslea trispora were systematically supplemented with putative, deuterium-labeled precursors downstream of beta-carotene en route to the bioactive TSAs. Analysis of the isolated metabolites allowed the reconstruction of the complete biosynthetic sequence between the first apocarotenoid, D'orenone (1), and the different series of TSAs B (8) and C (13). Both mating types produced a similar spectrum of early metabolites upstream of trisporols B (7) and C (12), while only the (+) type was able to further oxidize trisporols B (7) and C (12) to the corresponding methyltrisporoid B (5) and C (11), respectively. A novel 4-dihydrotrisporic acid B (14) that was not formed from the labeled precursors was isolated from mated strains; this compound might be derived from oxygenated beta-carotene by a parallel pathway. The ester accumulated in the culture broth of the (+) strain and was only hydrolyzed by mycelia of the (-) strain; this corresponds to a synchronization of the biosynthetic activities of both mating types.


Assuntos
Ácidos Graxos Insaturados/química , Mucorales/metabolismo , Ácidos Graxos Insaturados/biossíntese , Cromatografia Gasosa-Espectrometria de Massas , Cinética , Fenômenos Fisiológicos , Fatores Sexuais , Fatores de Tempo , beta Caroteno/química , beta Caroteno/metabolismo
9.
J Asian Nat Prod Res ; 10(7-8): 775-80, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18696331

RESUMO

Two new pyrrole alkaloids, N-[4-(2-formyl-5-hydroxymethyl-pyrrol-1-yl)-butyl]-acetamide (1) and N-[5-(2-formyl-5-hydroxymethyl-pyrrol-1-yl)-pentyl]-acetamide (2), and a new indole derivative (3aR,8aR)-3a-acetoxyl-1,2,3,3a,8,8a-hexahydropyrrolo-[2,3-b]indol (3) were isolated, together with ( - )-3a-hydroxyfuroindoline, (3aR,8aS)-1-acetyl-1,3,3a,8,8a-hexahydropyrrolo-[2,3-b]indol-3a-ol, and N-acetyltryptamine A, from an endophytic ascomycetous fungus, Fusarium incarnatum (HKI00504), which was isolated from the mangrove plant Aegiceras corniculatum. The structures of compounds 1-3 were determined on the basis of extensive spectroscopic data analyses.


Assuntos
Alcaloides/química , Fusarium/química , Indóis/química , Primulaceae/microbiologia , Pirróis/química , Estrutura Molecular
11.
J Nat Prod ; 71(4): 689-92, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18271552

RESUMO

In our ongoing search for new bioactive metabolites from microbial resources, Aspergillus terreus (HKI0499) was examined by chemical metabolite profiling. Together with the known butyrolactone I ( 3), the unusual sulfate derivatives butyrolactone I 3-sulfate ( 1) and butyrolactone I 4''-sulfate ( 2) were discovered. The chemical structures were determined by NMR and MS data analyses. All compounds were tested on CDK1/cyclin B, CDK5/p25, DYRK1A, CK1, and GSK-3alpha/beta kinases; compounds 2 and 3 were also evaluated for their cytotoxic and antiproliferative activities. Butyrolactone I 3-sulfate ( 1) exhibited specific inhibitory activity against CDK1/cyclin B and CDK5/p25, yet 15-30-fold less than butyrolactone I ( 3). Likewise, butyrolactone I 3-sulfate ( 1) exhibited moderate cytotoxicity solely against HeLa cells (CC 50 = 80.7 microM).


Assuntos
4-Butirolactona/análogos & derivados , Antineoplásicos/isolamento & purificação , Aspergillus/química , Sulfatos/química , 4-Butirolactona/química , 4-Butirolactona/isolamento & purificação , 4-Butirolactona/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Encéfalo/enzimologia , Proteína Quinase CDC2/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Ensaios de Seleção de Medicamentos Antitumorais , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Oócitos/enzimologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Estrelas-do-Mar/enzimologia , Suínos , Quinases Dyrk
12.
J Med Chem ; 50(21): 5168-75, 2007 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-17877337

RESUMO

Four new griseusins, 4'-dehydro-deacetylgriseusin A (1) and 2a,8a-epoxy-epi-deacetylgriseusin B (2) as new constitutional derivatives and epi-deacetylgriseusin A (3) and epi-deacetylgriseusin B (4) as new stereoisomers, were isolated from Nocardiopsis sp. (YIM80133, DSM16644). 4'-Dehydro-deacetylgriseusin A (1) showed pronounced cytotoxic potency (mean IC50 = 0.430 microM) combined with a significant selectivity for mammary cancer, renal cancer, and melanoma in a panel consisting of 37 tumor cell lines. In a clonogenic assay with tumor cells from 51 solid tumors, 1 inhibited anchorage independent growth and in vitro colony formation of tumor cells in a concentration-dependent and tumor type selective manner. As 1 was only a minor product, a semisynthetic preparation from the major metabolite, epi-deacetylgriseusin A (3), was achieved. Our studies also yielded 9-hydroxy-epi-deacetylgriseusin B methylester (5), 4'-dehydro-9-hydroxy-deacetylgriseusin B methylester (6), and 4'-dehydro-2a,8a-epoxy-deacetylgriseusin B (7) as new synthetic isochromanequinone derivatives, which provided a basic structure-activity relationship study.


Assuntos
Actinobacteria/química , Antibióticos Antineoplásicos/isolamento & purificação , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Naftoquinonas/química , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas
13.
Chemistry ; 11(19): 5523-30, 2005 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-15940739

RESUMO

Cervimycins A-D are novel polyketide glycosides with significant activity against multi-drug-resistant staphylococci and vancomycin-resistant enterococci. They are produced by a strain of Streptomyces tendae, isolated from an ancient cave. The structures of the cervimycins were determined by performing extensive NMR and chemical degradation studies. All cervimycins have a common tetracyclic polyketide core that is substituted with unusual di- and tetrasaccharide chains, composed exclusively of trideoxysugars; however, they differ in the acetyl and carbamoyl ring substituent and in the highly unusual terminal methylmalonyl and dimethylmalonyl residues.


Assuntos
Bactérias/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Resistência a Vancomicina/efeitos dos fármacos , Bactérias/classificação , Bactérias/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Glicosídeos/química , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrofotometria Infravermelho
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