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1.
J Antibiot (Tokyo) ; 67(7): 527-31, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24690911

RESUMO

The ever-increasing bacterial resistance to clinical antibiotics is making many drugs ineffective and creating significant treatment gaps. This can be only circumvented by the discovery of antibiotics with new mechanisms of action. We report here the identification of a new tetramic acid, ascosetin, from an Ascomycete using the Staphylococcus aureus fitness test screening method. The structure was elucidated by spectroscopic methods including 2D NMR and HRMS. Relative stereochemistry was determined by ROESY and absolute configuration was deduced by comparative CD spectroscopy. Ascosetin inhibited bacterial growth with 2-16 µg ml(-1) MIC values against Gram-positive strains including methicillin-resistant S. aureus. It also inhibited the growth of Haemophilus influenzae with a MIC value of 8 µg ml(-1). It inhibited DNA, RNA, protein and lipid synthesis with similar IC50 values, suggesting a lack of specificity; however, it produced neither bacterial membrane nor red blood cell lysis. It showed selectivity for bacterial growth inhibition compared with fungal but not mammalian cells. The isolation, structure and biological activity of ascosetin have been detailed here.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Antibacterianos/isolamento & purificação , Ascomicetos/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Conformação Molecular , Pirrolidinonas/isolamento & purificação , Staphylococcus aureus/efeitos dos fármacos
2.
J Nat Prod ; 77(3): 497-502, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24428261

RESUMO

Bacteria continue to evade existing antibiotics by acquiring resistance by various mechanisms, leading to loss of antibiotic effectiveness. To avoid an epidemic from infections of incurable drug-resistant bacteria, new antibiotics with new modes of action are desperately needed. Using a genome-wide mechanism of action-guided whole cell screening approach based on antisense Staphylococcus aureus fitness test technology, we report herein the discovery of altersolanol P (1), a new tetrahydroanthraquinone from an unknown fungus from the Hypocreales isolated from forest litter collected in Puerto Rico. The structure was elucidated by high-resolution mass spectrometry and 2D NMR spectroscopy. Relative stereochemistry was established by NOESY correlations, and absolute configuration was deduced by the application of MPA ester-based methodology. Observed (1)H and (13)C NMR shifts were well aligned with the corresponding chemical shifts predicted by DFT calculations. Altersolanol P exhibited Gram-positive antibacterial activity (MIC range 1-8 µg/mL) and inhibited the growth of Gram-negative Haemophilus influenzae (MIC 2 µg/mL). The isolation, structure elucidation, and antibacterial activity of altersolanol P are described.


Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Hypocreales/química , Staphylococcus aureus/efeitos dos fármacos , Antraquinonas/química , Antibacterianos/química , Farmacorresistência Bacteriana/efeitos dos fármacos , Haemophilus influenzae/efeitos dos fármacos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Porto Rico
3.
J Antibiot (Tokyo) ; 66(10): 599-607, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23801187

RESUMO

Natural products have been major sources of antibacterial agents and remain very promising. Frequent rediscoveries of known compounds hampers progress of new discoveries and demands development and utilization of new methods for rapid biological and chemical dereplication. This paper describes an efficient approach for discovery of new thiazolyl peptides by sensitive-resistant pair screening and dereplication in a time and cost-effective manner at industrial scale. A highly effective library-based dereplication of thiazolyl peptides by high resolution fourier transform liquid chromatography mass spectrometry (HRFTLCMS) has been developed, which can detect and dereplicate very low levels of thiazolyl peptides particularly when combined with miniaturized high-throughput 96-well solid-phase extraction separation, and as well can be automated. Combination of sensitive (susceptible)-resistant pair screening, diversified screening collection and miniaturized high-throughput SPE and HRFTLCMS techniques were applied for discovery of new thiazolyl peptides. The combined approach allowed for identification of over 24 thiazolyl peptides represented by three of the five structural subgroups, including three novel compounds. In addition, it is possible for the first time to mechanistically group three structural subgroups of over 24 thiazolyl peptides. Furthermore, these studies helped to understand natural frequency of distribution of these compounds and helped in discovery of new producing strains of many thiazolyl compounds.


Assuntos
Actinobacteria/metabolismo , Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Peptídeos Cíclicos/farmacologia , Peptídeos/farmacologia , Tiazóis/farmacologia , Antibacterianos/química , Antibacterianos/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Cromatografia Líquida , Farmacorresistência Bacteriana , Análise de Fourier , Ensaios de Triagem em Larga Escala/métodos , Espectrometria de Massas/métodos , Testes de Sensibilidade Microbiana/métodos , Peptídeos/química , Peptídeos/metabolismo , Tiazóis/química , Tiazóis/metabolismo
4.
Bioorg Med Chem Lett ; 22(23): 7127-30, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-23084277

RESUMO

Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family.


Assuntos
Aminoglicosídeos/isolamento & purificação , Aminoglicosídeos/farmacologia , Antibacterianos/química , Naftalenos/isolamento & purificação , Naftalenos/farmacologia , Actinomycetales/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Conformação Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II
5.
Methods Mol Biol ; 944: 79-96, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23065609

RESUMO

The FERMEX (Fermentation Extract) program was a highly successful source of microbial natural product molecules for pharmaceutical lead discovery. The program was based on the observation that solid fermentations of fungi generally exhibited more complex metabolite profiles than when the same strains were grown on liquid medium. To produce interference-free fermentations and improve organic product recovery, fungi colonized homogeneous media-saturated vermiculite thus promoting cellular and metabolic differentiation. Secondary metabolites in fungal cells were extracted from the substratum and medium with methyethylketone to generate metabolite-enriched screening samples. The necessary equipment, protocol, and media recipes are described along with examples of bioactive fungal metabolites produced in this system.


Assuntos
Produtos Biológicos/isolamento & purificação , Técnicas de Cultura/métodos , Fungos/crescimento & desenvolvimento , Fungos/metabolismo , Fermentação
6.
J Nat Prod ; 75(6): 1210-4, 2012 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-22694270

RESUMO

Three new cyclic tetrapeptides (1-3) have been isolated from the crude fermentation extract of Onychocola sclerotica. The planar structures of 1-3 were elucidated by detailed spectroscopic analyses using one- and two-dimensional NMR experiments and high-resolution mass spectrometry. The absolute configuration of the amino acid residues in each cyclotetrapeptide was established by Marfey's method. Compounds 1-3 displayed activity as cardiac calcium channel blockers (Cav1.2) but did not inhibit the hERG potassium channel and were not cytotoxic. These peptides are the first secondary metabolites ever reported from fungi of the order Arachnomycetales.


Assuntos
Ascomicetos/química , Peptídeos Cíclicos/isolamento & purificação , Vasodilatadores/isolamento & purificação , Aminoácidos , Canais de Cálcio Tipo L/efeitos dos fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Fermentação , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Vasodilatadores/química , Vasodilatadores/farmacologia
7.
Chem Biol ; 18(8): 955-65, 2011 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-21867911

RESUMO

Bacterial resistance to known therapeutics has led to an urgent need for new chemical classes of antibacterial agents. To address this we have applied a Staphylococcus aureus fitness test strategy to natural products screening. Here we report the discovery of kibdelomycin, a novel class of antibiotics produced by a new member of the genus Kibdelosporangium. Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity and is a potent inhibitor of DNA synthesis. We demonstrate through chemical genetic fitness test profiling and biochemical enzyme assays that kibdelomycin is a structurally new class of bacterial type II topoisomerase inhibitor preferentially inhibiting the ATPase activity of DNA gyrase and topoisomerase IV. Kibdelomycin is thus the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades.


Assuntos
Actinomycetales/química , Antibacterianos/química , Antibacterianos/farmacologia , Pirróis/química , Pirróis/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/enzimologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/isolamento & purificação , DNA Girase/metabolismo , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/metabolismo , Farmacorresistência Bacteriana , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Pirróis/isolamento & purificação , Pirrolidinonas/isolamento & purificação , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/genética , Inibidores da Topoisomerase II/isolamento & purificação
8.
J Antibiot (Tokyo) ; 63(8): 512-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20664605

RESUMO

Bacterial resistance to antibiotics, particularly to multiple antibiotics, is becoming a cause for significant concern. The only really viable course of action to counter this is to discover new antibiotics with novel modes of action. We have recently implemented a new antisense-based chemical genetic screening technology to accomplish this goal. The discovery and antibacterial activity of coelomycin, a fully substituted 2,6-dioxo pyrazine, illustrates the application of the Staphylococcus aureus fitness test strategy to natural products discovery.


Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Ascomicetos/metabolismo , Pirazinas/isolamento & purificação , Pirazinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Antibacterianos/química , Ascomicetos/isolamento & purificação , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Juniperus/microbiologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirazinas/química
9.
Bioorg Med Chem Lett ; 19(11): 3059-62, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19394221

RESUMO

Combinatorial biocatalysis was applied to generate a diverse set of dihydroxymethylzearalenone analogs with modified ring structure. In one representative chemoenzymatic reaction sequence, dihydroxymethylzearalenone was first subjected to a unique enzyme-catalyzed oxidative ring opening reaction that creates two new carboxylic groups on the molecule. These groups served as reaction sites for further derivatization involving biocatalytic ring closure reactions with structurally diverse bifunctional reagents, including different diols and diamines. As a result, a library of cyclic bislactones and bislactams was created, with modified ring structures covering chemical space and structure activity relationships unattainable by conventional synthetic means.


Assuntos
Zearalenona/química , Biocatálise , Desenho de Fármacos , Enzimas/metabolismo , Lipase/metabolismo , Relação Estrutura-Atividade , Zearalenona/biossíntese
10.
J Nat Prod ; 67(2): 228-31, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14987064

RESUMO

Four new congeners, rediocides B-E (2-5), of the previously reported rediocide A (1) were isolated from a methanol extract of the roots of the plant Trigonostemon reidioides. The structures of these minor analogues were elucidated by comparison of their NMR and mass spectral data with those of rediocide A and confirmed by extensive 2D NMR spectral analysis. They all possess potent activity against fleas (Ctenocephalides felis) in an artificial membrane feeding system and exhibited LD(90) values ranging from 0.25 to 0.5 ppm.


Assuntos
Diterpenos/isolamento & purificação , Euphorbiaceae/química , Inseticidas/isolamento & purificação , Plantas Medicinais/química , Sifonápteros , Animais , Culicidae , Diterpenos/química , Diterpenos/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Macrolídeos , Membranas Artificiais , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Raízes de Plantas/química , Estereoisomerismo , Tailândia
11.
J Nat Prod ; 66(1): 121-4, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12542359

RESUMO

Nodulisporic acids C (4a), C1 (5a), and C2 (6a), a series of D-ring-opened nodulisporic acids, were isolated from fermentations of a mutant culture of Nodulisporium sp. MF5954. Nodulisporic acid C, the most potent of the three, showed good activity against fleas with an LD90 of 10 micro g/mL. These compounds tend to be unstable in the free acid form and were isolated as stable sodium salts.


Assuntos
Antiparasitários/isolamento & purificação , Ascomicetos/química , Diterpenos/isolamento & purificação , Indóis/isolamento & purificação , Sifonápteros/efeitos dos fármacos , Animais , Antiparasitários/química , Antiparasitários/farmacologia , Ciclização , Diterpenos/química , Diterpenos/farmacologia , Indóis/química , Indóis/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 12(20): 2941-4, 2002 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-12270179

RESUMO

During the re-isolation of the lead compound nodulisporic acid A (1a) and targeted chemical screening for related compounds, we discovered a series of 1'-deoxy congeners named herein nodulisporic acids B (1b), B1 (2b), and B2 (3b). In comparison with nodulisporic acid A, these compounds were less active and were chemically unstable resulting into formation of delta23 dehydro derivatives. Therefore, these compounds were stabilized and isolated as sodium salts and methyl ester. Nodulisporic acid B is 100-fold less active than nodulisporic acid A against fleas. The isolation, structure elucidation, and biological activities of these compounds are described.


Assuntos
Ascomicetos/química , Indóis/química , Inseticidas/química , Animais , Ascomicetos/genética , Cromatografia por Troca Iônica , Indóis/isolamento & purificação , Inseticidas/isolamento & purificação , Inseticidas/toxicidade , Ivermectina/toxicidade , Espectroscopia de Ressonância Magnética , Mutação/genética , Sifonápteros , Estereoisomerismo
13.
J Org Chem ; 67(3): 815-25, 2002 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-11856024

RESUMO

Apicidins are a class of cyclic tetrapeptides that do not contain the classical electrophilic alpha-keto epoxide yet are potent (nM) inhibitors of histone deacetylase and antiprotozoal agents. These compounds showed broad-spectrum activities against the apicomplexan family of protozoa including Plasmodium sp (malarial parasite), Toxoplasma gondii, Cryptosporidium sp., and Eimeria sp. These cyclic peptides contain a beta-turn amino acid (R)-Pip or (R)-Pro, (S)-N-methoxy Trp, (S)-Ile, or (S)-Val, and either (S)-2-amino-8-oxodecanoic acid or a modified (S)-2-amino-8-oxodecanoic acid. The isolation and structure elucidation of new apicidins from two Fusarium species, temperature-dependent NMR studies of apicidin, NMR and molecular modeling based conformation of the 12-membered macrocyclic ring, and selected chemical modifications of apicidin have been detailed in this paper. The cyclic nature of the peptide, the C-8 keto group, and the tryptophan are all critical for the biological activity.


Assuntos
Antiprotozoários/química , Inibidores Enzimáticos/química , Compostos de Epóxi/química , Inibidores de Histona Desacetilases , Peptídeos Cíclicos/química , Antiprotozoários/farmacologia , Inibidores Enzimáticos/farmacologia , Espectrometria de Massas , Ressonância Magnética Nuclear Biomolecular , Peptídeos Cíclicos/farmacologia , Conformação Proteica , Estereoisomerismo
14.
J Org Chem ; 61(22): 7727-7737, 1996 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11667727

RESUMO

Farnesyl-protein transferase (FPTase) is an enzyme responsible for the farnesylation of Ras protein. Farnesylation is required for cell-transforming activity in several tumor-types, and therefore, inhibition of FPTase activity may be a potential target for anticancer drugs. Our continued search for novel inhibitors led to the isolation of a number of bicyclic resorcinaldehyde cyclohexanone derivatives named here cylindrols A(1) to A(4), cylindrols B and B(1), and a number of known compounds, from Cylindrocarpon lucidum. The compounds were isolated by bioassay-guided separation using Sephadex LH-20, silica gel, and reverse phase HPLC. Structures were elucidated by extensive application of 2D NMR and X-ray crystallography. The determination of absolute stereochemistry was accomplished by CD measurements. Chemical transformations of the most abundant compound resulted in a number of key derivatives which were critical for the evaluation of structure activity relationship. These compounds are members of ascochlorin family and showed a wide range of inhibitory activity (0.7 &mgr;M to >140 &mgr;M) against FPTase. The FPTase activity was noncompetitive with respect to both substrates. Isolation, structures, chemical transformations, and FPTase activity are discussed in detail.

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