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1.
mBio ; 11(3)2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32371599

RESUMO

The vaginal microbiota influences sexual transmission of human immunodeficiency virus type 1 (HIV-1). Colonization of the vaginal tract is normally dominated by Lactobacillus species. Both Lactobacillus and Enterococcus faecalis may secrete reutericyclin, which inhibits the growth of a variety of pathogenic bacteria. Increasing evidence suggests a potential therapeutic role for an analogue of reutericyclin, glycerol monolaurate (GML), against microbial pathogens. Previous studies using a macaque vaginal simian immunodeficiency virus (SIV) transmission model demonstrated that GML reduces transmission and alters immune responses to infection in vitro Previous studies showed that structural analogues of GML negatively impact other enveloped viruses. We sought to expand understanding of how GML inhibits HIV-1 and other enveloped viruses and show that GML restricts HIV-1 entry post-CD4 engagement at the step of coreceptor binding. Further, HIV-1 and yellow fever virus (YFV) particles were more sensitive to GML interference than particles "matured" by proteolytic processing. We show that high-pressure-liquid-chromatography (HPLC)-purified reutericyclin and reutericyclin secreted by Lactobacillus inhibit HIV-1. These data emphasize the importance and protective nature of the normal vaginal flora during viral infections and provide insights into the antiviral mechanism of GML during HIV-1 infection and, more broadly, to other enveloped viruses.IMPORTANCE A total of 340 million sexually transmitted infections (STIs) are acquired each year. Antimicrobial agents that target multiple infectious pathogens are ideal candidates to reduce the number of newly acquired STIs. The antimicrobial and immunoregulatory properties of GML make it an excellent candidate to fit this critical need. Previous studies established the safety profile and antibacterial activity of GML against both Gram-positive and Gram-negative bacteria. GML protected against high-dose SIV infection and reduced inflammation, which can exacerbate disease, during infection. We found that GML inhibits HIV-1 and other human-pathogenic viruses (yellow fever virus, mumps virus, and Zika virus), broadening its antimicrobial range. Because GML targets diverse infectious pathogens, GML may be an effective agent against the broad range of sexually transmitted pathogens. Further, our data show that reutericyclin, a GML analog expressed by some lactobacillus species, also inhibits HIV-1 replication and thus may contribute to the protective effect of Lactobacillus in HIV-1 transmission.


Assuntos
Antivirais/farmacologia , Lactobacillus/metabolismo , Lauratos/farmacologia , Monoglicerídeos/farmacologia , Proteínas do Envelope Viral/metabolismo , Vírus/efeitos dos fármacos , Animais , Antivirais/metabolismo , Feminino , HIV-1/efeitos dos fármacos , HIV-1/metabolismo , HIV-1/fisiologia , Humanos , Lauratos/metabolismo , Monoglicerídeos/metabolismo , Receptores Virais/metabolismo , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/metabolismo , Ácido Tenuazônico/farmacologia , Vagina/microbiologia , Ligação Viral , Internalização do Vírus , Vírus/metabolismo
2.
Sci Rep ; 9(1): 14550, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601928

RESUMO

Human milk has antimicrobial compounds and immunomodulatory activities. We investigated glycerol monolaurate (GML) in human milk versus bovine milk and infant formula for antimicrobial and anti-inflammatory activities. Human milk contained approximately 3000 µg/ml of GML, compared to 150 µg/ml in bovine milk and none in infant formula. For bacteria tested (Staphylococcus aureus, Bacillus subtilis, Clostridium perfringens, Escherichia coli), except Enterococcus faecalis, human milk was more antimicrobial than bovine milk and formula. The Enterococcus faecalis strain, which was not inhibited, produced reutericyclin, which is an analogue of GML and functions as a growth stimulant in bacteria that produce it. Removal of GML and other lipophilic molecules from human milk by ethanol extraction resulted in a loss of antibacterial activity, which was restored by re-addition of GML. GML addition caused bovine milk to become antimicrobial. Human milk but not bovine milk or formula inhibited superantigen and bacterial-induced IL-8 production by model human epithelial cells. GML may contribute beneficially to human milk compared to bovine milk or infant formula.


Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Lauratos/farmacologia , Leite Humano/química , Monoglicerídeos/farmacologia , Animais , Bacillus subtilis/efeitos dos fármacos , Bovinos , Clostridium perfringens/efeitos dos fármacos , Enterococcus faecalis/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Inflamação , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/metabolismo
3.
Chemistry ; 25(44): 10333-10341, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31187904

RESUMO

(5S,6S)-Aminotenuazonic acid, a new 3-acyltetramic acid, related to the well-known mycotoxin tenuazonic acid has been isolated from fruiting bodies of Laccaria bicolor. Its structure was mostly established by analysis of its 2D NMR and HR-(+)-ESI-MS spectra. A total synthesis starting from N-Boc-l-isoleucine gave (5S,6S)-aminotenuazonic acid in 8 % yield over nine steps (67 % de). The key steps of the total synthesis are a light-initiated Hofmann-Löffler-Freytag radical chain reaction and a Dieckmann cyclisation. The relative and absolute configurations of the natural product were determined by comparison of its NMR and CD spectra with those of the corresponding enantiopure synthetic compounds. Metabolic profiling of crude extracts of different mushrooms showed that aminotenuazonic acid is present in all four of the investigated Laccaria species. Aminotenuazonic acid shows phytotoxic activities against the root and shoot growth of Lepidium sativum, Pinus sylvestris and Arabidopsis thaliana comparable to those of tenuazonic acid.


Assuntos
Carpóforos/química , Herbicidas/isolamento & purificação , Laccaria/química , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/isolamento & purificação , Arabidopsis , Catálise , Ciclização , Herbicidas/síntese química , Lepidium sativum , Oxirredução , Pinus sylvestris , Raízes de Plantas , Brotos de Planta , Ácido Tenuazônico/síntese química
4.
Chemistry ; 23(24): 5692-5695, 2017 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-28345765

RESUMO

3-Acyltetramic acids derived from ß-hydroxytyrosine are synthetically challenging. The first route to this structural motif, based upon a condensation between a Meldrum's acid conjugate bearing the acyl side chain, and a ß-hydroxytyrosinate, N-protected by an ortho-nitrobenzyl group is presented. This group enables the Dieckmann cyclization of the resulting N-(ß-ketoacyl)amino ester, after which it can be removed photolytically without compromising the delicate 3'-hydroxy group. This strategy was applied to the first total synthesis of the fungal metabolite F-14329 (1).


Assuntos
Fungos/metabolismo , Pirrolidinonas/química , Ácido Tenuazônico/análogos & derivados , Produtos Biológicos/síntese química , Produtos Biológicos/química , Ciclização , Paecilomyces/metabolismo , Pirrolidinonas/síntese química , Estereoisomerismo , Ácido Tenuazônico/síntese química , Ácido Tenuazônico/química
5.
Sci Rep ; 6: 37479, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27869143

RESUMO

Streptococcus mutans is a major pathogen causing human dental caries. As a Gram-positive bacterium with a small genome (about 2 Mb) it is considered a poor source of natural products. Due to a recent explosion in genomic data available for S. mutans strains, we were motivated to explore the natural product production potential of this organism. Bioinformatic characterization of 169 publically available genomes of S. mutans from human dental caries revealed a surprisingly rich source of natural product biosynthetic gene clusters. Anti-SMASH analysis identified one nonribosomal peptide synthetase (NRPS) gene cluster, seven polyketide synthase (PKS) gene clusters and 136 hybrid PKS/NRPS gene clusters. In addition, 211 ribosomally synthesized and post-translationally modified peptides (RiPPs) clusters and 615 bacteriocin precursors were identified by a combined analysis using BAGEL and anti-SMASH. S. mutans harbors a rich and diverse natural product genetic capacity, which underscores the importance of probing the human microbiome and revisiting species that have traditionally been overlooked as "poor" sources of natural products.


Assuntos
Produtos Biológicos/metabolismo , Vias Biossintéticas , Mineração de Dados , Genômica , Boca/microbiologia , Streptococcus mutans/genética , Sequência de Aminoácidos , Bacteriocinas/química , Bacteriocinas/farmacologia , Produtos Biológicos/farmacologia , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Genes Bacterianos , Humanos , Família Multigênica , Filogenia , Alinhamento de Sequência , Streptococcus mutans/efeitos dos fármacos , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/química , Ácido Tenuazônico/farmacologia
6.
Future Med Chem ; 7(14): 1861-77, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26431450

RESUMO

The emergence of antimicrobial resistance has created a need for the development of novel antibacterial therapies to treat infection. Natural products that exhibit antibacterial activity offer validated starting points for library generation, and the authors report here that small molecule mimics of tetramate-containing natural products may show antibacterial activity and offer the potential for further optimization.


Assuntos
Antibacterianos/química , Produtos Biológicos/química , Antibacterianos/farmacologia , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Fenótipo , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/química , Ácido Tenuazônico/farmacologia , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologia
7.
J Antimicrob Chemother ; 70(11): 3061-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26286574

RESUMO

OBJECTIVES: Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. METHODS: A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. RESULTS: Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole. CONCLUSIONS: This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases.


Assuntos
Antibacterianos/farmacocinética , Infecções por Clostridium/tratamento farmacológico , Colo/química , Metronidazol/farmacocinética , Pirrolidinonas/farmacocinética , Ácido Tenuazônico/análogos & derivados , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Modelos Animais de Doenças , Masculino , Mesocricetus , Metronidazol/administração & dosagem , Metronidazol/química , Pirrolidinonas/química , Ácido Tenuazônico/química , Ácido Tenuazônico/farmacocinética , Resultado do Tratamento
8.
Appl Environ Microbiol ; 81(6): 2032-41, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25576609

RESUMO

Reutericyclin is a unique antimicrobial tetramic acid produced by some strains of Lactobacillus reuteri. This study aimed to identify the genetic determinants of reutericyclin biosynthesis. Comparisons of the genomes of reutericyclin-producing L. reuteri strains with those of non-reutericyclin-producing strains identified a genomic island of 14 open reading frames (ORFs) including genes coding for a nonribosomal peptide synthetase (NRPS), a polyketide synthase (PKS), homologues of PhlA, PhlB, and PhlC, and putative transport and regulatory proteins. The protein encoded by rtcN is composed of a condensation domain, an adenylation domain likely specific for d-leucine, and a thiolation domain. rtcK codes for a PKS that is composed of a ketosynthase domain, an acyl-carrier protein domain, and a thioesterase domain. The products of rtcA, rtcB, and rtcC are homologous to the diacetylphloroglucinol-biosynthetic proteins PhlABC and may acetylate the tetramic acid moiety produced by RtcN and RtcK, forming reutericyclin. Deletion of rtcN or rtcABC in L. reuteri TMW1.656 abrogated reutericyclin production but did not affect resistance to reutericyclin. Genes coding for transport and regulatory proteins could be deleted only in the reutericyclin-negative L. reuteri strain TMW1.656ΔrtcN, and these deletions eliminated reutericyclin resistance. The genomic analyses suggest that the reutericyclin genomic island was horizontally acquired from an unknown source during a unique event. The combination of PhlABC homologues with both an NRPS and a PKS has also been identified in the lactic acid bacteria Streptococcus mutans and Lactobacillus plantarum, suggesting that the genes in these organisms and those in L. reuteri share an evolutionary origin.


Assuntos
Antibacterianos/biossíntese , Vias Biossintéticas , Lactobacillus reuteri/genética , Lactobacillus reuteri/metabolismo , Ácido Tenuazônico/análogos & derivados , DNA Bacteriano/química , DNA Bacteriano/genética , Deleção de Genes , Ilhas Genômicas , Lactobacillus plantarum/genética , Dados de Sequência Molecular , Fases de Leitura Aberta , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Streptococcus mutans/genética , Ácido Tenuazônico/biossíntese
9.
J Antibiot (Tokyo) ; 68(6): 399-402, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25627017
10.
Sci Rep ; 4: 4721, 2014 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-24739957

RESUMO

Whilst the development of membrane-active antibiotics is now an attractive therapeutic concept, progress in this area is disadvantaged by poor knowledge of the structure-activity relationship (SAR) required for optimizing molecules to selectively target bacteria. This prompted us to explore the SAR of the Lactobacillus reuteri membrane-active antibiotic reutericyclin, modifying three key positions about its tetramic acid core. The SAR revealed that lipophilic analogs were generally more active against Gram-positive pathogens, but introduction of polar and charged substituents diminished their activity. This was confirmed by cytometric assays showing that inactive compounds failed to dissipate the membrane potential. Radiolabeled substrate assays indicated that dissipation of the membrane potential by active reutericyclins correlated with inhibition of macromolecular synthesis in cells. However, compounds with good antibacterial activities also showed cytotoxicity against Vero cells and hemolytic activity. Although this study highlights the challenge of optimizing membrane-active antibiotics, it shows that by increasing antibacterial potency the selectivity index could be widened, allowing use of lower non-cytotoxic doses.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Membranas/efeitos dos fármacos , Ácido Tenuazônico/análogos & derivados , Animais , Antibacterianos/química , Chlorocebus aethiops , Humanos , Lactobacillus reuteri/química , Membranas/química , Relação Estrutura-Atividade , Ácido Tenuazônico/química , Ácido Tenuazônico/farmacologia , Células Vero
11.
Chem Commun (Camb) ; 50(13): 1588-90, 2014 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-24382380

RESUMO

A range of N-acylpyrrolo[3,4-c]isoxazoles and derived N-acyltetramides has been prepared via a nitrile oxide dipolar cycloaddition approach, as analogues of the acyltetramic acid metabolite reutericyclin, of interest for its antibiotic potential against Gram-positive bacteria including hospital-acquired infections of resistant Clostridium difficile.


Assuntos
Antibacterianos/química , Ácido Tenuazônico/análogos & derivados , Antibacterianos/síntese química , Enterocolite Pseudomembranosa/tratamento farmacológico , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Lactobacillus/química , Modelos Moleculares , Ácido Tenuazônico/síntese química , Ácido Tenuazônico/química
12.
J Chromatogr A ; 1289: 27-36, 2013 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-23578482

RESUMO

Analogues of the Alternaria mycotoxin tenuazonic acid (TA, biosynthesized by the fungus from the amino acid isoleucine) derived from valine (ValTA), leucine (LeuTA), alanine (AlaTA) and phenylalanine (PheTA) were synthesized and characterized by mass spectrometry (MS) and (1)H nuclear magnetic resonance (NMR) spectroscopy. Concentrations of stock solutions were determined by quantitative (1)H NMR (qHNMR). Two analytical methods based on high performance liquid chromatography (HPLC) and MS detection were developed, one with derivatization with 2,4-dinitrophenylhydrazine (DNPH) and one without derivatization. Limits of detection (LODs) were between 1-3 µg/kg (with derivatization) and 50-80 µg/kg (without derivatization). Respective limits of quantitation (LOQs) were about three times higher. Beside TA, the analogues LeuTA (about 4% of TA content) and ValTA (about 10% of TA content) were found in highly contaminated sorghum infant cereals and sorghum grains. Other analogues were not detected. Quantification of LeuTA and ValTA was performed using [(13)C6,(15)N]-TA as internal standard and matrix matched calibration. Recovery was between 95±11% and 102±10% for both compounds. Precision (relative standard deviation of triplicate sorghum cereal analyses three times during 3 weeks) was 7% for TA (912±60 µg/kg), 17% for LeuTA (43±8 µg/kg) and 19% for ValTA (118±22 µg/kg). These results indicate that several TA-like compounds, which are not yet characterized in aspects of their toxic properties, were detected in sorghum based infant food highly contaminated with TA, already.


Assuntos
Alternaria/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Grão Comestível/química , Contaminação de Alimentos/análise , Espectrometria de Massas/métodos , Micotoxinas/análogos & derivados , Ácido Tenuazônico/análogos & derivados , Alimentos Infantis/análise , Limite de Detecção , Espectroscopia de Ressonância Magnética , Micotoxinas/metabolismo , Sorghum/química , Ácido Tenuazônico/metabolismo
13.
Food Microbiol ; 34(1): 46-51, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23498177

RESUMO

The effects of high pressure, temperature, and antimicrobial compounds on endospores of Clostridium spp. were examined. Minimal inhibitory concentrations (MIC) of nisin and reutericyclin were determined for vegetative cells and endospores of Clostridium sporogenes ATCC 7955, Clostridium beijerinckii ATCC 8260, and Clostridium difficile 3195. Endospores of C. sporogenes ATCC 7955 and C. beijerinckii ATCC 8260 were exposed to 90 °C and 90 °C/600 MPa in the presence of 16 mg L(-1) nisin or 6.4 mg L(-1) reutericyclin for 0-60 min in a 0.9% saline solution. Dipicolinic acid (DPA) release was measured using a terbium-DPA fluorescence assay, and endospore permeability was assessed using 4',6-diamidino-2-phenylindole (DAPI) fluorescence. Vegetative cells of C. sporogenes ATCC 7955 exhibited higher sensitivity to nisin relative to endospores, with MIC values 0.23 ± 0.084 mg L(-1) and 1.11 ± 0.48 mg L(-1), respectively. Nisin increased DPA release when endospores were treated at 90 °C; however, only C. sporogenes ATCC 7955 exhibited higher inactivation, suggesting strain or species specific effects. Reutericyclin did not enhance spore inactivation or DPA release. Use of nisin in combination with high pressure, thermal treatments enhanced inactivation of endospores of Clostridium spp. and may have application in foods.


Assuntos
Antibacterianos/farmacologia , Clostridium/efeitos dos fármacos , Nisina/farmacologia , Ácido Tenuazônico/análogos & derivados , Clostridium/química , Clostridium/crescimento & desenvolvimento , Temperatura Alta , Viabilidade Microbiana/efeitos dos fármacos , Pressão , Esporos Bacterianos/química , Esporos Bacterianos/efeitos dos fármacos , Esporos Bacterianos/crescimento & desenvolvimento , Ácido Tenuazônico/farmacologia
14.
Appl Environ Microbiol ; 79(6): 2103-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23335780

RESUMO

This study determined the membrane fluidity of clostridial endospores during treatment with heat and pressure with nisin or reutericyclin. Heating (90°C) reduced laurdan (6-dodecanoyl-2-dimethylaminonaphthalene) general polarization, corresponding to membrane fluidization. Pressure (200 MPa) stabilized membrane order. Reutericyclin and nisin exhibit divergent effects on heat- and pressure-induced spore inactivation and membrane fluidity.


Assuntos
Clostridium/fisiologia , Fluidez de Membrana/efeitos dos fármacos , Fluidez de Membrana/efeitos da radiação , Esporos Bacterianos/fisiologia , 2-Naftilamina/análogos & derivados , 2-Naftilamina/metabolismo , Clostridium/efeitos dos fármacos , Clostridium/efeitos da radiação , Temperatura Alta , Pressão Hidrostática , Lauratos/metabolismo , Viabilidade Microbiana/efeitos dos fármacos , Viabilidade Microbiana/efeitos da radiação , Nisina/metabolismo , Esporos Bacterianos/efeitos dos fármacos , Esporos Bacterianos/efeitos da radiação , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/metabolismo
15.
J Antimicrob Chemother ; 68(4): 806-15, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23264511

RESUMO

OBJECTIVES: The stationary phase of Clostridium difficile, which is primarily responsible for diarrhoeal symptoms, is refractory to antibiotic killing. We investigated whether disrupting the functions of the clostridial membrane is an approach to control C. difficile infections by promptly removing growing and non-growing cells. METHODS: The bactericidal activities of various membrane-active agents were determined against C. difficile logarithmic-phase and stationary-phase cultures and compared with known antibiotics. Their effects on the synthesis of ATP, toxins A/B and sporulation were also determined. The effect of rodent caecal contents on anti-difficile activities was examined using two reutericyclin lead compounds, clofazimine, daptomycin and other comparator antibiotics. RESULTS: Most membrane-active agents and partially daptomycin showed concentration-dependent killing of both logarithmic-phase and stationary-phase cultures. The exposure of cells to compounds at their MBC resulted in a rapid loss of viability with concomitant reductions in cellular ATP, toxins A/B and spore numbers. With the exception of nisin, these effects were not due to membrane pore formation. Interestingly, the activity of the proton ionophore nigericin significantly increased as the growth of C. difficile decreased, suggesting the importance of the proton gradient to the survival of non-growing cells. The activities of the lipophilic antimicrobials reutericyclins and clofazimine were reduced by caecal contents. CONCLUSIONS: These findings indicate that C. difficile is uniquely susceptible to killing by molecules affecting its membrane function and bioenergetics, indicating that the clostridial membrane is a novel antimicrobial target for agents to alleviate the burden of C. difficile infections.


Assuntos
Antibacterianos/administração & dosagem , Membrana Celular/efeitos dos fármacos , Infecções por Clostridium/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Carga Bacteriana , Ceco/microbiologia , Clofazimina , Infecções por Clostridium/microbiologia , Cricetinae , Mesocricetus , Viabilidade Microbiana/efeitos dos fármacos , Ácido Tenuazônico/administração & dosagem , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/farmacologia
16.
Plant Physiol Biochem ; 52: 38-51, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22305066

RESUMO

3-Acetyl-5-isopropyltetramic acid (3-AIPTA), a derivate of tetramic acid, is responsible for brown leaf-spot disease in many plants and often kills seedlings of both mono- and dicotyledonous plants. To further elucidate the mode of action of 3-AIPTA, during 3-AIPTA-induced cell necrosis, a series of experiments were performed to assess the role of reactive oxygen species (ROS) in this process. When Arabidopsis thaliana leaves were incubated with 3-AIPTA, photosystem II (PSII) electron transport beyond Q(A) (the primary plastoquinone acceptor of PSII) and the reduction of the end acceptors at the PSI acceptor side were inhibited; this was followed by increase in charge recombination and electron leakage to O(2), resulting in chloroplast-derived oxidative burst. Furthermore, the main antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) lost their activity. Excess ROS molecules directly attacked a variety of cellular components and subsequently caused electrolyte leakage, lipid peroxidation and cell membrane disruption. Finally, this led to cell destruction and leaf tissue necrosis. Thus, 3-AIPTA-triggered leaf necrosis of Arabidopsis was found to be a result of direct oxidative injury from the chloroplast-originated ROS burst initiated by the inhibition of normal photosynthetic electron transport.


Assuntos
Arabidopsis/efeitos dos fármacos , Arabidopsis/fisiologia , Cloroplastos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Ácido Tenuazônico/análogos & derivados , Antioxidantes/metabolismo , Arabidopsis/enzimologia , Ascorbato Peroxidases/efeitos dos fármacos , Ascorbato Peroxidases/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular , Cloroplastos/efeitos dos fármacos , Transporte de Elétrons/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Complexo de Proteína do Fotossistema II/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/enzimologia , Folhas de Planta/metabolismo , Plântula/efeitos dos fármacos , Plântula/enzimologia , Plântula/metabolismo , Superóxido Dismutase/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Ácido Tenuazônico/farmacologia
17.
J Antimicrob Chemother ; 66(8): 1773-6, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21632577

RESUMO

OBJECTIVES: The stationary phase of Clostridium difficile, which is associated with the symptoms of the diarrhoeal disease, is refractory to antibiotic killing. The aim of this study was to explore whether probiotic-derived reutericyclin and related synthetic analogues could kill stationary phase C. difficile at concentrations achievable in the gastrointestinal tract. METHODS: The bactericidal activities of reutericyclin and lead compound derivatives were examined against logarithmic and stationary phase cultures of different C. difficile strains. The absorption of compounds across the intestinal epithelia was tested using the Caco-2 permeability model. RESULTS: Unlike vancomycin and metronidazole, reutericyclins demonstrated concentration-dependent killing, being rapidly bactericidal against both logarithmic and stationary phase cells, at low concentrations (0.09-2 mg/L). The intestinal absorption of unmodified reutericyclin was poor and comparable to that of vancomycin. However, this property varied significantly for the synthetic reutericyclin analogues, ranging from well absorbed to non-absorbed. The non-absorbable compounds were highly effluxed, suggesting this parameter could be modulated to obtain agents with superior efficacy. CONCLUSIONS: Reutericyclins showed excellent potency against the lethal non-growing stage of C. difficile at concentrations that may be attained in the gastrointestinal tract. Since these agents represent novel potential treatments for C. difficile infection, further development of this compound class is warranted.


Assuntos
Antibacterianos/farmacologia , Antibacterianos/farmacocinética , Colo/química , Viabilidade Microbiana/efeitos dos fármacos , Ácido Tenuazônico/análogos & derivados , Células CACO-2 , Humanos , Ácido Tenuazônico/farmacocinética , Ácido Tenuazônico/farmacologia
18.
Nat Prod Commun ; 4(11): 1473-6, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19967976

RESUMO

From the medicinal plant Ginkgo biloba the fungal endophyte Alternaria no.28 was isolated. Extract of the fungus grown in liquid culture media exhibited marked cytotoxic activity when tested in vitro against brine shrimp (Artemia salina). Eight compounds were isolated from the extract of cultures of this endophytic fungus and were elucidated as alterperylenol (1), altertoxin I (2), alternariol (3), alternariol monomethyl ether (4), tenuazonic acid (5) and its derivative (6), together with ergosterol and ergosta-4, 6, 8, 22-tetraen-3-one by means of spectroscopic analysis. Among them, both 5 and 6 showed significant cytotoxic effects in the brine shrimp bioassy, with mortality rates of 73.6% and 68.9%, respectively, at a concentration of 10 microg x mL(-1), and they were first isolated from endophytic fungi.


Assuntos
Alternaria/metabolismo , Antibióticos Antineoplásicos/biossíntese , Antibióticos Antineoplásicos/farmacologia , Ginkgo biloba/microbiologia , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/biossíntese , Ácido Tenuazônico/farmacologia , Animais , Artemia , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray
19.
Antimicrob Agents Chemother ; 53(9): 4028-31, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19581456

RESUMO

The potential for reutericyclin derivatives to be used as topical antibiotics to treat staphylococcal skin infections was investigated. All reutericyclins inhibited the growth of clinical isolates of drug-resistant Staphylococcus aureus. Unlike the standard topical agent mupirocin, most reutericyclin derivatives eradicated staphylococcal biofilms. Moreover, two compounds formulated in hydrophilic petrolatum (10%, wt/wt) were efficacious in treating S. aureus superficial skin infections in mice. These data exemplify the prospect of developing reutericyclins as new topical antibiotics.


Assuntos
Antibacterianos/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Linhagem Celular , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Pirrolidinonas/farmacologia , Pirrolidinonas/uso terapêutico , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/química , Ácido Tenuazônico/farmacologia , Ácido Tenuazônico/uso terapêutico
20.
Syst Appl Microbiol ; 29(2): 89-99, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16464690

RESUMO

The effect of environmental conditions on the production of homo-polysaccharides and oligosaccharides from sucrose and the regulation of glycosyltransferase genes responsible for biosynthesis of homo-polysaccharides was determined in Lactobacillus reuteri TMW1.106 (reutericyclin-producer) and LTH5448 (reutericyclin-negative). Strain L. reuteri TMW 1.106 harbours the glycosyltransferase genes gtfA and inu, strain LTH5448 harbours a fructosyltransferase, ftfA. Fructan and fructose-oligosaccharide (FOS) production in both strains was inducible by reutericyclin, trans-isohumulone, and nigericin at the levels of their minimum inhibitory concentrations (MIC) as well as phenylethanol (6mM) and elevated growth temperatures (45 degrees C), but not by nisin, CCCP or gramicidin. Elevated temperature (45 degrees C), reutericyclin or trans-isohumulone but not CCCP furthermore increased enhanced inu and ftfA transcription in L. reuteri TMW1.106 and LTH5448, respectively. Generally, effects of the various agents on fructosyltransferase transcription corresponded to their effect on formation of poly and oligosaccharides from sucrose. The effect of membrane-active agents on fructosyltransferase expression was compared to their effect on membrane biophysical parameters. The ability of chemical and physical agents to induce expression of fructosyltransferases correlated to their effect on the membrane lateral pressure as measured by pyrene-labelled phospholipids in membrane vesicles. Dextran, levan and fructose-oligosaccharides added at 50gL(-1) protected L. reuteri towards the membrane-active inhibitors nisin, reutericyclin, and CCCP. The induction of glycosyltransferases by membrane stress indicates a protective role of fructans and FOS to lactobacilli exposed to physical and chemical environmental stressors.


Assuntos
Hexosiltransferases/metabolismo , Ionóforos/farmacologia , Lactobacillus reuteri/metabolismo , Ciclopentanos/farmacologia , Frutanos/metabolismo , Hexosiltransferases/genética , Lactobacillus reuteri/efeitos dos fármacos , Nigericina/farmacologia , Oligossacarídeos/metabolismo , Temperatura , Ácido Tenuazônico/análogos & derivados , Ácido Tenuazônico/farmacologia
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