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Fosfito de potássio no controle de Phytophthora spp. em citros e faia e seu modo de ação; Potassium phosphite in the control of Phytophthora spp. in citrus and beech plants and its mode of action

Rezende, Dalilla Carvalho
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 29/01/2015 PT
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95.65%
A citricultura brasileira ocupa lugar de destaque no agronegócio nacional, sendo o país o maior produtor de laranja e suco de laranja do mundo. A faia (Fagus sylvatica) é uma das principais espécies das florestas na Europa, sendo usada como ornamental e por possui alto valor econômico devido à produção de madeira. Um dos principais entraves no cultivo dessas espécies é a ocorrência de doenças principalmente as causadas por espécies de Phytophthora que além de causar grandes prejuízos, os métodos de controle são difíceis e onerosos. Existem trabalhos na literatura que apontam os fosfitos como alternativa sustentável, eficaz e economicamente viável para o controle de doenças causadas por oomicetos. Entretanto, o Comitê de Ação a Resistência à Fungicidas (FRAC) classifica os fosfitos, como produtos com ingrediente ativo sem mecanismo de ação definido. Neste contexto, este trabalho teve como objetivo avaliar o produto comercial à base de fosfito de potássio, Phytogard® no controle das doenças causadas por Phytophthora nicotianae em citros e Phytophthora plurivora em faia, bem como avaliar através de análises bioquímicas se esse produto induz resistência em plântulas de citros. Além disso, foram realizados estudos in vitro para avaliar o efeito direto do Phytogard® sobre o desenvolvimento de P. nicotianae e P. plurivora e verificar os possíveis mecanismos de ação desse produto sobre esses patógenos. Foram utilizadas plântulas de citros e faia que foram aspergidas com diferentes concentrações de Phytogard® e...

Mode of Action of Pulegone on the Urinary Bladder of F344 Rats

Da Rocha, Mitscheli S.; Dodmane, Puttappa R.; Arnold, Lora L.; Pennington, Karen L.; Anwar, Muhammad M.; Adams, Bret R.; Taylor, Sean V.; Wermes, Clint; Adams, Timothy B.; Cohen, Samuel M.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
ENG
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Essential oils from mint plants, including peppermint and pennyroyal oils, are used at low levels as flavoring agents in various foods and beverages. Pulegone is a component of these oils. In a 2-year bioassay, oral administration of pulegone slightly increased the urothelial tumor incidence in female rats. We hypothesized that its mode of action (MOA) involved urothelial cytotoxicity and increased cell proliferation, ultimately leading to tumors. Pulegone was administered by gavage at 0, 75, or 150 mg/kg body weight to female rats for 4 and 6 weeks. Fresh void urine and 18-h urine were collected for crystal and metabolite analyses. Urinary bladders were evaluated by light microscopy and scanning electron microscopy (SEM) and bromodeoxyuridine (BrdU) labeling index. Pulegone and its metabolites, piperitenone, piperitone, menthofuran, and menthone, were tested for cytotoxicity in rat (MYP3) and human (1T1) urothelial cells by the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. No abnormal urinary crystals were observed by light microscopy. Urine samples (18-h) showed the presence of pulegone, piperitone, piperitenone, and menthofuran in both treated groups. By SEM...

Antibacterial activity and mode of action of selected glucosinolate hydrolysis products against bacterial pathogens

Borges, Anabela; Abreu, Ana C.; Ferreira, Carla; Saavedra, Maria J.; Simões, Lúcia C.; Simões, Manuel
Fonte: Scientific Publishers Publicador: Scientific Publishers
Tipo: Artigo de Revista Científica
Publicado em //2015 ENG
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Plants contain numerous components that are important sources of new bioactive molecules with antimicrobial properties. Isothiocyanates (ITCs) are plant secondary metabolites found in cruciferous vegetables that are arising as promising antimicrobial agents in food industry. The aim of this study was to assess the antibacterial activity of two isothiocyanates (ITCs), allylisothiocyanate (AITC) and 2-phenylethylisothiocyanate (PEITC) against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Listeria monocytogenes. The antibacterial mode of action was also characterized by the assessment of different physiological indices: membrane integrity, intracellular potassium release, physicochemical surface properties and surface charge. The minimum inhibitory concentration (MIC) of AITC and PEITC was 100 g/mL for all bacteria. The minimum bactericidal concentration (MBC) of the ITCs was at least 10 times higher than the MIC. Both AITC and PEITC changed the membrane properties of the bacteria decreasing their surface charge and compromising the integrity of the cytoplasmatic membrane with consequent potassium leakage and propidium iodide uptake. The surface hydrophobicity was also non-specifically altered (E. coli and L. monocytogenes become less hydrophilic; P. aeruginosa and S. aureus become more hydrophilic). This study shows that AITC and PEITC have strong antimicrobial potential against the bacteria tested...

Life-history responses of Daphnia magna Straus to binary mixtures of toxic substances: Pharmacological versus ecotoxicological modes of action

Barata, Carlos; Baird, Donald J.; Nogueira, António J. A.; Agra, Ana Raquel; Soares, Amadeu M. V. M.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artigo de Revista Científica
ENG
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85.66%
Two prevailing theoretical models: concentration addition (CA) and independent action (IA), predict mixture toxicity on the basis of known toxicities of the mixture components. To date, both models have been in most occasions evaluated using unicellular in vivo responses or biochemical in vitro responses. However, when considering more complex models such as the whole organism physiology or life-history traits, the dominant ecotoxicological mode of action, based on the exposure concentrations at which various toxicological effects become operative at the level of whole organism, should be considered. Offspring production in Daphnia magna is driven by the resources acquired from food, and the number of live offspring produced by an organism is the result of two independent factors: the number of eggs produced and the percentage of eggs that survive egg development. In this study joint toxicity effects on offspring production in D. magna were tested using binary mixtures of toxic contaminants known to specifically impair food acquisition (lambda-cyhalothrin and cadmium) or to cause egg mortality during development (3,4 dichloroaniline). Tests were performed using a simplified 10-day reproduction assay initiated with gravid females. The results obtained indicate that irrespective of their primary pharmacological mode of action...

Study of modes of action of the biocontrol agent metschnikowia and auensis pbc-2

Manso, Teresa; Vero, Silvana; González, M. Belén; Nunes, Carla
Fonte: Universidade do Algarve Publicador: Universidade do Algarve
Tipo: Parte de Livro
Publicado em //2010 ENG
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Proceedings of the International Conference “Environmentally friendly and safe technologies for quality of fruit and vegetables”, held in Universidade do Algarve, Faro, Portugal, on January 14-16, 2009. This Conference was a join activity with COST Action 924.; Metschnikowia andauensis NCYC 3728 (PBC-2) is an effective antagonist against the postharvest pathogens Penicillium expansum, Botrytis cinerea and Rhizopus stolofiner on pome fruits, however its mode of action is unknown. The ability of this strain to produce inhibitory compounds in 4 distinct media (PDA, NYDA, YPDA, CJA) at 3 temperatures (1, 25, 30 ºC), was investigated. It was also assayed the competition for iron in media with different iron concentrations and characterized the capability of PBC-2 produce and secrete fungal cell wall lytic enzymes, like chitinase, protease, and glucanase in a culture media with fungal pathogen cell wall as unique carbon source. M. andauensis PBC-2 did not show any inhibition zone to cope pathogens in any of the tested media. The results obtained in this study suggest that the production and secretion of lytic enzymes is not the main or more important mode of action of the new biocontrol agent PBC-2, since the production of chitinase was observed only past 5 and 7 d of incubation...

Bacteriocins from Lactobacillus plantarum production, genetic organization and mode of action: produção, organização genética e modo de ação

Todorov,Svetoslav D.
Fonte: Sociedade Brasileira de Microbiologia Publicador: Sociedade Brasileira de Microbiologia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2009 EN
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Bacteriocins are biologically active proteins or protein complexes that display a bactericidal mode of action towards usually closely related species. Numerous strains of bacteriocin producing Lactobacillus plantarum have been isolated in the last two decades from different ecological niches including meat, fish, fruits, vegetables, and milk and cereal products. Several of these plantaricins have been characterized and the aminoacid sequence determined. Different aspects of the mode of action, fermentation optimization and genetic organization of the bacteriocin operon have been studied. However, numerous of bacteriocins produced by different Lactobacillus plantarum strains have not been fully characterized. In this article, a brief overview of the classification, genetics, characterization, including mode of action and production optimization for bacteriocins from Lactic Acid Bacteria in general, and where appropriate, with focus on bacteriocins produced by Lactobacillus plantarum, is presented.

Mode of Action of Sulfanilyl Fluoroquinolones

Alovero, Fabiana; Nieto, Marcelo; Mazzieri, Maria Rosa; Then, Rudolf; Manzo, Ruben H.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /06/1998 EN
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The mode of action of sulfanilyl fluoroquinolones (NSFQs) was investigated with NSFQ-104, NSFQ-105, and some structurally related compounds. Evidence arising from interactions with p-aminobenzoic acid and trimethoprim suggested that a sulfonamidelike mechanism of action makes little or no contribution to the in vitro activity of NSFQs. NSFQ-105 showed an activity that inhibits gyrase-catalyzed DNA supercoiling that is similar to the activity of other fluoroquinolones. Also, NSFQ-105 uptake was decreased by the presence of Mg2+ and increased by a lower pH. These results indicate that NSFQs having only one ionizable group could exhibit more favorable kinetics of access to the bacterial cell than zwitterionic fluoroquinolones.

Mode of Action of a Structurally Novel Beta-Lactam

Presslitz, Joseph E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1978 EN
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CP-35,587 {6-[d-2-amino-2-(p-hydroxyphenyl)acetamido]-2,2-dimethyl-3- (5-tetrazolyl)-penam} is a member of a new family of β-lactam antibacterial agents. Because the biospectrum of CP-35,587 has features similar to both penicillins and cephalosporins, experiments were carried out to explore its mode of action. CP-35,587 did not inhibit peptidoglycan transpeptidase from Escherichia coli, but it did inhibit dd-carboxypeptidase. Similar results were obtained with cephalexin. When these antibiotics were compared for effects on growth and morphology of E. coli, it was observed that filaments formed after exposure to either antibacterial agent for 30 to 60 min. The filaments enlarged, and fragmentation occurred until very few viable cells remained after exposure to CP-35,587. After 180 min in the presence of cephalexin, the cells began to divide, and the filaments formed cross-walls reaching control values in 24 h. CP-35,587 and cephalexin had similar effects on the morphology of the Klebsiella cell: the cells became enlarged within 30 min; with increasing exposure, the filaments became longer, with evidence of cytoplasmic emptying and ghost cell formation. These ghostlike tubules eventually broke apart, leaving fragments. These data indicate differences in the mode of action of CP-35...

Unraveling the Mode of Action of the Antimalarial Choline Analog G25 in Plasmodium falciparum and Saccharomyces cerevisiae

Roggero, Rodolphe; Zufferey, Rachel; Minca, Mihaela; Richier, Eric; Calas, Michele; Vial, Henri; Mamoun, Choukri Ben
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /08/2004 EN
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Pharmacological studies have indicated that the choline analog G25 is a potent inhibitor of Plasmodium falciparum growth in vitro and in vivo. Although choline transport has been suggested to be the target of G25, the exact mode of action of this compound is not known. Here we show that, similar to its effects on P. falciparum, G25 prevents choline entry into Saccharomyces cerevisiae cells and inhibits S. cerevisiae growth. However, we show that the uptake of this compound is not mediated by the choline carrier Hnm1. An hnm1Δ yeast mutant, which lacks the only choline transporter gene HNM1, was not altered in the transport of a labeled analog of this compound. Eleven yeast mutants lacking genes involved in different steps of phospholipid biosynthesis were analyzed for their sensitivity to G25. Four mutants affected in the de novo cytidyldiphosphate-choline-dependent phosphatidylcholine biosynthetic pathway and, surprisingly, a mutant strain lacking the phosphatidylserine decarboxylase-encoding gene PSD1 (but not PSD2) were found to be highly resistant to this compound. Based on these data for S. cerevisiae, labeling studies in P. falciparum were performed to examine the effect of G25 on the biosynthetic pathways of the major phospholipids phosphatidylcholine and phosphatidylethanolamine. Labeling studies in P. falciparum and in vitro studies with recombinant P. falciparum phosphatidylserine decarboxylase further supported the inhibition of both the de novo phosphatidylcholine metabolic pathway and the synthesis of phosphatidylethanolamine from phosphatidylserine. Together...

Studies on the Mode of Action of the Antifungal Hexapeptide PAF26

Muñoz, Alberto; López-García, Belén; Marcos, Jose F.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2006 EN
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85.61%
The small antimicrobial peptide PAF26 (Ac-RKKWFW-NH2) has been identified by a combinatorial approach and shows preferential activity toward filamentous fungi. In this work, we investigated the mode of action and inhibitory effects of PAF26 on the fungus Penicillium digitatum. The dye Sytox Green was used to demonstrate that PAF26 induced cell permeation. However, microscopic observations showed that sub-MIC concentrations of PAF26 produced both alterations of hyphal morphology (such as altered polar growth and branching) and chitin deposition in areas of no detectable permeation. Analysis of dose-response curves of inhibition and permeation suggested that growth inhibition is not solely a consequence of permeation. In order to shed light on the mode of PAF26 action, its antifungal properties were compared with those of melittin, a well-known pore-forming peptide that kills through cytolysis. While the 50% inhibitory concentrations and MICs of the two peptides against P. digitatum mycelium were comparable, they differed markedly in their fungicidal activities toward conidia and their hemolytic activities toward human red blood cells. Kinetic studies showed that melittin quickly induced Penicillium cell permeation, while PAF26-induced Sytox Green uptake was significantly slower and less efficient. Therefore...

Leishmania donovani Polyamine Biosynthetic Enzyme Overproducers as Tools To Investigate the Mode of Action of Cytotoxic Polyamine Analogs▿

Roberts, Sigrid C.; Jiang, Yuqui; Gasteier, Judith; Frydman, Benjamin; Marton, Laurence J.; Heby, Olle; Ullman, Buddy
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
EN
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85.56%
A number of anticancer and antiparasitic drugs are postulated to target the polyamine biosynthetic pathway and polyamine function, but the exact mode of action of these compounds is still being elucidated. To establish whether polyamine analogs specifically target enzymes of the polyamine pathway, a model was developed using strains of the protozoan parasite Leishmania donovani that overproduce each of the polyamine biosynthetic enzymes. Promastigotes overexpressing episomal constructs encoding ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (ADOMETDC), or spermidine synthase (SPDSYN) revealed robust overproduction of the corresponding polyamine biosynthetic enzyme. Polyamine pools, however, were either unchanged or only marginally affected, implying that regulatory mechanisms must exist. The ODC, ADOMETDC, and SPDSYN overproducer strains exhibited a high level of resistance to difluoromethylornithine, 5′-{[(Z)-4-amino-2-butenyl]methylamino}-5′-deoxyadenosine, and n-butylamine, respectively, confirming previous observations that these agents specifically target polyamine enzymes. Conversely, augmented levels of polyamine biosynthetic enzymes did not affect the sensitivity of L. donovani promastigotes to pentamidine...

Dermcidin-Derived Peptides Show a Different Mode of Action than the Cathelicidin LL-37 against Staphylococcus aureus▿

Senyürek, Ilknur; Paulmann, Maren; Sinnberg, Tobias; Kalbacher, Hubert; Deeg, Martin; Gutsmann, Thomas; Hermes, Marina; Kohler, Thomas; Götz, Fritz; Wolz, Christiane; Peschel, Andreas; Schittek, Birgit
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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Dermcidin (DCD) is an antimicrobial peptide which is constitutively expressed in eccrine sweat glands. By postsecretory proteolytic processing in sweat, the DCD protein gives rise to anionic and cationic DCD peptides with a broad spectrum of antimicrobial activity. Many antimicrobial peptides induce membrane permeabilization as part of their killing mechanism, which is accompanied by a loss of the bacterial membrane potential. In this study we show that there is a time-dependent bactericidal activity of anionic and cationic DCD-derived peptides which is followed by bacterial membrane depolarization. However, DCD-derived peptides do not induce pore formation in the membranes of gram-negative and gram-positive bacteria. This is in contrast to the mode of action of the cathelicidin LL-37. Interestingly, LL-37 as well as DCD-derived peptides inhibit bacterial macromolecular synthesis, especially RNA and protein synthesis, without binding to microbial DNA or RNA. Binding studies with components of the cell envelope of gram-positive and gram-negative bacteria and with model membranes indicated that DCD-derived peptides bind to the bacterial envelope but show only a weak binding to lipopolysaccharide (LPS) from gram-negative bacteria or to peptidoglycan...

Antibacterial Properties and Mode of Action of a Short Acyl-Lysyl Oligomer▿

Zaknoon, Fadia; Sarig, Hadar; Rotem, Shahar; Livne, Liran; Ivankin, Andrey; Gidalevitz, David; Mor, Amram
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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We investigated the potency, selectivity, and mode of action of the oligo-acyl-lysine (OAK) NC12-2β12, which was recently suggested to represent the shortest OAK sequence that retains nonhemolytic antibacterial properties. A growth inhibition assay against a panel of 48 bacterial strains confirmed that NC12-2β12 exerted potent activity against gram-positive bacteria while exhibiting negligible hemolysis up to at least 100 times the MIC. Interestingly, NC12-2β12 demonstrated a bacteriostatic mode of action, unlike previously described OAKs that were bactericidal and essentially active against gram-negative bacteria only. The results of various experiments with binding to model phospholipid membranes correlated well with those of the cytotoxicity experiments and provided a plausible explanation for the observed activity profile. Thus, surface plasmon resonance experiments performed with model bilayers revealed high binding affinity to a membrane composition that mimicked the plasma membrane of staphylococci (global affinity constant [Kapp], 3.7 × 106 M−1) and significantly lower affinities to mimics of Escherichia coli or red blood cell cytoplasmic membranes. Additional insertion isotherms and epifluorescence microscopy experiments performed with model Langmuir monolayers mimicking the outer leaflet of plasma membranes demonstrated the preferential insertion of NC12-2β12 into highly anionic membranes. Finally...

Role of Plasmodium falciparum Digestive Vacuole Plasmepsins in the Specificity and Antimalarial Mode of Action of Cysteine and Aspartic Protease Inhibitors ▿ †

Moura, Pedro A.; Dame, John B.; Fidock, David A.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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85.56%
Hemoglobin (Hb) degradation is essential for the growth of the intraerythrocytic stages of malarial parasites. This process, which occurs inside an acidic digestive vacuole (DV), is thought to involve the action of four aspartic proteases, termed plasmepsins (PMs). These enzymes have received considerable attention as potential antimalarial drug targets. Leveraging the availability of a set of PM-knockout lines generated in Plasmodium falciparum, we report here that a wide range of previously characterized or novel aspartic protease inhibitors exert their antimalarial activities independently of their effect on the DV PMs. We also assayed compounds previously shown to inhibit cysteine proteases residing in the DV. The most striking observation was a ninefold increase in the potency of the calpain inhibitor N-acetyl-leucinyl-leucinyl-norleucinal (ALLN) against parasites lacking all four DV PMs. Genetic ablation of PM III or PM IV also decreased the level of parasite resistance to the β-hematin binding antimalarial chloroquine. On the basis of the findings of drug susceptibility and isobologram assays, as well as the findings of studies of the inhibition of Hb degradation, morphological analyses, and stage specificity, we conclude that the DV PMs and falcipain cysteine proteases act cooperatively in Hb hydrolysis. We also identify several aspartic protease inhibitors...

Deciphering the Mode of Action of the Synthetic Antimicrobial Peptide Bac8c▿

Spindler, E. C.; Hale, J. D. F.; Giddings, T. H.; Hancock, R. E. W.; Gill, R. T.
Fonte: American Society for Microbiology (ASM) Publicador: American Society for Microbiology (ASM)
Tipo: Artigo de Revista Científica
EN
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Bac8c (RIWVIWRR-NH2) is an 8-amino-acid peptide derived from Bac2A (RLARIVVIRVAR-NH2), a C3A/C11A variant of the naturally occurring bovine peptide, bactenecin (also known as bovine dodecapeptide), the smallest peptide with activity against a range of pathogenic Gram-positive and Gram-negative bacteria, as well as yeast. The effects of Bac8c on Escherichia coli were examined by studying its bacteriostatic and bactericidal properties, demonstrating its effects on proton motive force generation, and visually analyzing (via transmission electron microscopy) its effects on cells at different concentrations, in order to probe the complexities of the mechanism of action of Bac8c. Results were consistent with a two-stage model for the Bac8c mode of action. At sublethal concentrations (3 μg/ml), Bac8c addition resulted in transient membrane destabilization and metabolic imbalances, which appeared to be linked to inhibition of respiratory function. Although sublethal concentrations resulted in deleterious downstream events, such as methylglyoxal formation and free radical generation, native E. coli defense systems were sufficient for full recovery within 2 h. In contrast, at the minimal bactericidal concentration (6 μg/ml), Bac8c substantially but incompletely depolarized the cytoplasmic membrane within 5 min and disrupted electron transport...

Mode of Action, In Vitro Activity, and In Vivo Efficacy of AFN-1252, a Selective Antistaphylococcal FabI Inhibitor

Kaplan, Nachum; Albert, Monique; Awrey, Donald; Bardouniotis, Elias; Berman, Judd; Clarke, Teresa; Dorsey, Mandy; Hafkin, Barry; Ramnauth, Jaillal; Romanov, Vladimir; Schmid, Molly B.; Thalakada, Rosanne; Yethon, Jeremy; Pauls, Henry W.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /11/2012 EN
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The mechanism of action of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), which is involved in fatty acid biosynthesis, was confirmed by using biochemistry, macromolecular synthesis, genetics, and cocrystallization of an AFN-1252–FabI complex. AFN-1252 demonstrated a low propensity for spontaneous resistance development and a time-dependent reduction of the viability of both methicillin-susceptible and methicillin-resistant S. aureus, achieving a ≥2-log10 reduction in S. aureus counts over 24 h, and was extremely potent against clinical isolates of S. aureus (MIC90, 0.015 μg/ml) and coagulase-negative staphylococci (MIC90, 0.12 μg/ml), regardless of their drug resistance, hospital- or community-associated origin, or other clinical subgroup. AFN-1252 was orally available in mouse pharmacokinetic studies, and a single oral dose of 1 mg/kg AFN-1252 was efficacious in a mouse model of septicemia, providing 100% protection from an otherwise lethal peritoneal infection of S. aureus Smith. A median effective dose of 0.15 mg/kg indicated that AFN-1252 was 12 to 24 times more potent than linezolid in the model. These studies, demonstrating a selective mode of action, potent in vitro activity...

Investigations of the Mode of Action and Resistance Development of Cadazolid, a New Antibiotic for Treatment of Clostridium difficile Infections

Locher, Hans H.; Caspers, Patrick; Bruyère, Thierry; Schroeder, Susanne; Pfaff, Philippe; Knezevic, Andreja; Keck, Wolfgang; Ritz, Daniel
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /02/2014 EN
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Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment of Clostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development in C. difficile strains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from different C. difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally <10−10 at 2× to 4× the MIC), and in multiple-passage experiments (up to 13 passages) MICs did not significantly increase. Furthermore, no cross-resistance was observed, as cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid...

Charakterisierung onkologischer Medikamentenkandidaten durch Analyse der zellulären Signalübertragung; Comprehensive signal transduction analysis for defining the mode of action of novel anticancer drugs

Heubach, Yvonne
Fonte: Universidade de Tubinga Publicador: Universidade de Tubinga
Tipo: Dissertação
DE_DE
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Das Potential neuartiger Antitumorsubstanzen kann nur durch detaillierte Analyse ihrer Wirkmechanismen voll ausgeschöpft werden. Umfassende Aktivitätsbestimmungen zellulärer Signalwegsproteine bereits in frühen Phasen der Medikamentenentwicklung eignen sich hierfür besonders. Durch Verbindung des dreidimensionalen Tumorsphäroid-Modells mit einer Mikroarray-basierten Proteinanalytik wurden in dieser Arbeit komplexe Signaltransduktionsanalysen auf Material ermöglicht, welches die Situation in humanen Tumormetastasen widerspiegelt. Dabei wurde die Wirkung von Medikamentenkandidaten aus frühen klinischen Entwicklungsphasen eingehend auf humanen Kolontumorsphäroiden analysiert. Ein Inhibitor des mitotischen Kinesins Eg5 zeigte neben dem für diese Substanzklasse typischen mitotischen Arrest der Zellen weitere relevante Effekte. Translationsinduktion durch aktivierte mTOR- und MAPK-Signalwege sowie Induktion von Ki-67 und Phosphorylierung von Rb deuteten auf eine Überführung ruhender Zellen in den aktiven Zellzyklus hin. Der Eg5-Inhibitor scheint somit den proliferativen Zustand von Zellen zu adressieren: Während ruhende Zellen (z.B. im Sphäroidinneren) in den aktiven Zellzyklus überführt und zur Proliferation angeregt werden...

A New Cephalosporin with a Dual Mode of Action

O'Callaghan, Cynthia H.; Sykes, R. B.; Staniforth, Susan E.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1976 EN
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A cephalosporin, (6R,7R)-7-[(2R)-2-hydroxy-2-phenylacetamido]-3-(pyrid-2-yl-N-oxide) thiomethylceph-3-em-4-carboxylic acid (MCO), that could lead to a novel approach to the problem of β-lactamase destruction is described. The compound is slightly more resistant to some β-lactamases than is cephalothin, but it is still hydrolyzed by many to a varying degree. Hydrolysis of the β-lactam bond of a cephalosporin releases the 3-substituent, which in MCO is itself an antibacterial agent, 2-mercaptopyridine-N-oxide. Thus, MCO has a dual mode of action, and bacteria that do not produce an effective amount of a β-lactamase are inhibited by the intact cephalosporin, whereas those that do hydrolyze it are inhibited by the released antibacterial compound.

Life-history responses of Daphnia magna Straus to binary mixtures of toxic substances: Pharmacological versus ecotoxicological modes of action

Barata Martí, Carlos; Baird, Donald J.; Nogueira, Antonio J. A.; Agra, Ana Raquel; Soares, Amadeu M. V. M.
Fonte: Elsevier Publicador: Elsevier
Tipo: Artículo Formato: 162 bytes; application/msword
ENG
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11 pages, 3 tables, 4 figures.-- PMID: 17720258 [PubMed].; Two prevailing theoretical models: concentration addition (CA) and independent action (IA), predict mixture toxicity on the basis of known toxicities of the mixture components. To date, both models have been in most occasions evaluated using unicellular in vivo responses or biochemical in vitro responses. However, when considering more complex models such as the whole organism physiology or life-history traits, the dominant ecotoxicological mode of action, based on the exposure concentrations at which various toxicological effects become operative at the level of whole organism, should be considered. Offspring production in Daphnia magna is driven by the resources acquired from food, and the number of live offspring produced by an organism is the result of two independent factors: the number of eggs produced and the percentage of eggs that survive egg development. In this study joint toxicity effects on offspring production in D. magna were tested using binary mixtures of toxic contaminants known to specifically impair food acquisition (λ-cyhalothrin and cadmium) or to cause egg mortality during development (3,4 dichloroaniline). Tests were performed using a simplified 10-day reproduction assay initiated with gravid females. The results obtained indicate that irrespective of their primary pharmacological mode of action...