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Brent R Copp - One of the best experts on this subject based on the ideXlab platform.

  • spermine derivatives of indole 3 carboxylic Acid indole 3 acetic Acid and indole 3 acrylic Acid as gram negative antibiotic adjuvants
    ChemMedChem, 2021
    Co-Authors: Melissa M Cadelis, Marielise Bourguetkondracki, Marine Blanchet, Hana Douafer, Jean Michel Brunel, Brent R Copp
    Abstract:

    The discovery of new antibiotic adjuvants is an attractive option for overcoming antimicrobial resistance. We have previously reported the discovery of a bis-6-bromoindolglyoxylamide derivative of spermine as being able to enhance the action of antibiotics against Gram-negative bacteria but suffers from being cytotoxic and red-blood cell haemolytic. A series of analogues was prepared exploring variation of the indolglyoxylamide unit, to include indole-3-acrylic, indole-3-acetic and indole-3-carboxylate units, and evaluated for antibiotic enhancing properties against a range of Gram-negative bacteria, and for intrinsic antimicrobial, cytotoxic and haemolytic properties. Two spermine derivatives, bearing 5-bromo-indole-3-acetic Acid (17) and 5-methoxy-indole-3-acrylic Acid (14) end groups were found to exhibit good to moderate antibiotic adjuvant activities for doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, but with more modest intrinsic antimicrobial activity and greatly reduced cytotoxic and haemolytic properties. The mechanism of action of the latter derivative identified its ability to disrupt the outer membranes of bacteria and to inhibit the AcrAB-TolC efflux pump directly or by inhibiting the proton gradient.

Rebecca A. Butcher - One of the best experts on this subject based on the ideXlab platform.

  • tryptophan metabolism in caenorhabditis elegans links aggregation behavior to nutritional status
    ACS Chemical Biology, 2019
    Co-Authors: Yue Zhou, Xinxing Zhang, Rebecca A. Butcher
    Abstract:

    Caenorhabditis elegans uses aggregation pheromones to communicate its nutritional status and recruit fellow members of its species to food sources. These aggregation pheromones include the IC-ascarosides, ascarosides modified with an indole-3-carbonyl (IC) group on the 4′-position of the ascarylose sugar. Nothing is known about the biosynthesis of the IC modification beyond the fact that it is derived from tryptophan. Here, we show that C. elegans produces endogenously several indole-containing metabolites, including indole-3-pyruvic Acid (IPA), indole-3-acetic Acid (IAA; auxin), and Indole-3-Carboxylic Acid, and that these metabolites are intermediates in the biosynthetic pathway from tryptophan to the IC group. Stable isotope-labeled IPA and IAA are incorporated into the IC-ascarosides. Importantly, we show that flux through the biosynthetic pathway is affected by the activity of the pyruvate dehydrogenase complex (PDC). Knockdown of the PDC by RNA interference leads to an accumulation of upstream metab...

  • Tryptophan Metabolism in Caenorhabditis elegans Links Aggregation Behavior to Nutritional Status
    2018
    Co-Authors: Yue Zhou, Xinxing Zhang, Rebecca A. Butcher
    Abstract:

    Caenorhabditis elegans uses aggregation pheromones to communicate its nutritional status and recruit fellow members of its species to food sources. These aggregation pheromones include the IC-ascarosides, ascarosides modified with an indole-3-carbonyl (IC) group on the 4′-position of the ascarylose sugar. Nothing is known about the biosynthesis of the IC modification beyond the fact that it is derived from tryptophan. Here, we show that C. elegans produces endogenously several indole-containing metabolites, including indole-3-pyruvic Acid (IPA), indole-3-acetic Acid (IAA; auxin), and Indole-3-Carboxylic Acid, and that these metabolites are intermediates in the biosynthetic pathway from tryptophan to the IC group. Stable isotope-labeled IPA and IAA are incorporated into the IC-ascarosides. Importantly, we show that flux through the biosynthetic pathway is affected by the activity of the pyruvate dehydrogenase complex (PDC). Knockdown of the PDC by RNA interference leads to an accumulation of upstream metabolites and a reduction in downstream metabolites in the pathway. Our results show that production of aggregation pheromones is linked to PDC activity and that aggregation behavior may reflect a favorable metabolic state in the worm. Lastly, we show that treatment of C. elegans with indole-containing metabolites in the pathway induces the biosynthesis of the IC-ascarosides. Because the natural environment of C. elegans is rotting plant material, indole-containing metabolites in this environment could potentially stimulate pheromone biosynthesis and aggregation behavior in the worm. Thus, there may be important links between tryptophan metabolism in C. elegans and in plants and bacteria that enable interkingdom signaling

Melissa M Cadelis - One of the best experts on this subject based on the ideXlab platform.

  • spermine derivatives of indole 3 carboxylic Acid indole 3 acetic Acid and indole 3 acrylic Acid as gram negative antibiotic adjuvants
    ChemMedChem, 2021
    Co-Authors: Melissa M Cadelis, Marielise Bourguetkondracki, Marine Blanchet, Hana Douafer, Jean Michel Brunel, Brent R Copp
    Abstract:

    The discovery of new antibiotic adjuvants is an attractive option for overcoming antimicrobial resistance. We have previously reported the discovery of a bis-6-bromoindolglyoxylamide derivative of spermine as being able to enhance the action of antibiotics against Gram-negative bacteria but suffers from being cytotoxic and red-blood cell haemolytic. A series of analogues was prepared exploring variation of the indolglyoxylamide unit, to include indole-3-acrylic, indole-3-acetic and indole-3-carboxylate units, and evaluated for antibiotic enhancing properties against a range of Gram-negative bacteria, and for intrinsic antimicrobial, cytotoxic and haemolytic properties. Two spermine derivatives, bearing 5-bromo-indole-3-acetic Acid (17) and 5-methoxy-indole-3-acrylic Acid (14) end groups were found to exhibit good to moderate antibiotic adjuvant activities for doxycycline towards the Gram-negative bacteria Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae, but with more modest intrinsic antimicrobial activity and greatly reduced cytotoxic and haemolytic properties. The mechanism of action of the latter derivative identified its ability to disrupt the outer membranes of bacteria and to inhibit the AcrAB-TolC efflux pump directly or by inhibiting the proton gradient.

Azair Cantodesouza - One of the best experts on this subject based on the ideXlab platform.

  • similar anxiolytic like effects following intra amygdala infusions of benzodiazepine receptor agonist and antagonist evidence for the release of an endogenous benzodiazepine inverse agonist in mice exposed to elevated plus maze test
    Brain Research, 2009
    Co-Authors: Cilene Aparecida Barbalho, Ricardo Luiz Nunesdesouza, Azair Cantodesouza
    Abstract:

    Abstract Previous studies have demonstrated that microinjections of midazolam, a benzodiazepine receptor agonist, into the amygdala produce anxiolytic-like effects in elevated plus-maze (EPM)-naive rodents. However, systemic or intracerebral administration of benzodiazepines (BDZ) fails to alter anxiety in maze-experienced animals, a phenomenon defined as “one trial tolerance” (OTT). This study focused on the effects of intra-amygdala infusion of midazolam in maze-experienced mice. In addition, the effects of flumazenil in the amygdala of maze-naive and experienced mice were also investigated. To investigate intrinsic effects of intra-amygdala flumazenil on anxiety, animals were systemically treated with the BDZ receptor inverse agonist, DMCM (4-ethyl-6,7-dimethoxy-9H-pyrido[3,4-b]Indole-3-Carboxylic Acid methyl ester hydrochloride). Conventional measures of anxiety (% open arm entries and % open arm time), locomotor activity (frequency of closed arm entries) and a range of ethological measures related to risk assessment were recorded. Intra-amygdala midazolam (3.0 and 30 nmol) attenuated anxiety in maze-experienced mice. A similar behavioral profile was produced by intra-amygdala flumazenil in maze-naive (4.0 and 16 nmol) and maze-experienced (16 nmol) mice. Intra-amygdala flumazenil (at 2.0 nmol, a dose devoid of any intrinsic effect on anxiety measures in the EPM) selectively and completely blocked the anxiogenic-like effects of systemic administration of DMCM (1.0 mg/kg, i.p.) in maze-naive mice. Together, these results demonstrate that the GABA A -benzodiazepine receptor complex located within the amygdala does not play a role in the OTT phenomenon. Present results also suggest that the release of an endogenous BDZ receptor inverse agonist within the amygdala seems to be an important correlate of the emotional state induced by the plus-maze test.

Yue Zhou - One of the best experts on this subject based on the ideXlab platform.

  • tryptophan metabolism in caenorhabditis elegans links aggregation behavior to nutritional status
    ACS Chemical Biology, 2019
    Co-Authors: Yue Zhou, Xinxing Zhang, Rebecca A. Butcher
    Abstract:

    Caenorhabditis elegans uses aggregation pheromones to communicate its nutritional status and recruit fellow members of its species to food sources. These aggregation pheromones include the IC-ascarosides, ascarosides modified with an indole-3-carbonyl (IC) group on the 4′-position of the ascarylose sugar. Nothing is known about the biosynthesis of the IC modification beyond the fact that it is derived from tryptophan. Here, we show that C. elegans produces endogenously several indole-containing metabolites, including indole-3-pyruvic Acid (IPA), indole-3-acetic Acid (IAA; auxin), and Indole-3-Carboxylic Acid, and that these metabolites are intermediates in the biosynthetic pathway from tryptophan to the IC group. Stable isotope-labeled IPA and IAA are incorporated into the IC-ascarosides. Importantly, we show that flux through the biosynthetic pathway is affected by the activity of the pyruvate dehydrogenase complex (PDC). Knockdown of the PDC by RNA interference leads to an accumulation of upstream metab...

  • Tryptophan Metabolism in Caenorhabditis elegans Links Aggregation Behavior to Nutritional Status
    2018
    Co-Authors: Yue Zhou, Xinxing Zhang, Rebecca A. Butcher
    Abstract:

    Caenorhabditis elegans uses aggregation pheromones to communicate its nutritional status and recruit fellow members of its species to food sources. These aggregation pheromones include the IC-ascarosides, ascarosides modified with an indole-3-carbonyl (IC) group on the 4′-position of the ascarylose sugar. Nothing is known about the biosynthesis of the IC modification beyond the fact that it is derived from tryptophan. Here, we show that C. elegans produces endogenously several indole-containing metabolites, including indole-3-pyruvic Acid (IPA), indole-3-acetic Acid (IAA; auxin), and Indole-3-Carboxylic Acid, and that these metabolites are intermediates in the biosynthetic pathway from tryptophan to the IC group. Stable isotope-labeled IPA and IAA are incorporated into the IC-ascarosides. Importantly, we show that flux through the biosynthetic pathway is affected by the activity of the pyruvate dehydrogenase complex (PDC). Knockdown of the PDC by RNA interference leads to an accumulation of upstream metabolites and a reduction in downstream metabolites in the pathway. Our results show that production of aggregation pheromones is linked to PDC activity and that aggregation behavior may reflect a favorable metabolic state in the worm. Lastly, we show that treatment of C. elegans with indole-containing metabolites in the pathway induces the biosynthesis of the IC-ascarosides. Because the natural environment of C. elegans is rotting plant material, indole-containing metabolites in this environment could potentially stimulate pheromone biosynthesis and aggregation behavior in the worm. Thus, there may be important links between tryptophan metabolism in C. elegans and in plants and bacteria that enable interkingdom signaling