The Experts below are selected from a list of 1119 Experts worldwide ranked by ideXlab platform
Larry Pedersen - One of the best experts on this subject based on the ideXlab platform.
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squalamine is not a Proton Ionophore
Biochimica et Biophysica Acta, 2000Co-Authors: Barry S. Selinsky, Andrea Frangiosi, Beth Vonbaur, Rob Smith, Larry PedersenAbstract:Abstract Squalamine, an aminosterol antibiotic isolated from the dogfish shark, creates relatively large defects in phospholipid bilayers, allowing the unrestricted translocation of small molecules across these compromised membranes (B.S. Selinsky, Z. Zhou, K.G. Fotjik, S.R. Jones, N.R. Dollahon, A.E. Shinnar, Biochim. Biophys. Acta 1370 (1998) 218–234). However, an aminosterol structurally similar to squalamine was found to act as a Proton Ionophore in anionic phospholipid vesicles. In contrast with squalamine, gross membrane disruption was not observed with this synthetic analog (G. Deng, T. Dewa, S.L. Regen, J. Am. Chem. Soc. 118 (1996) 8975–8976). In this report, the ionophoric activity of squalamine was tested in anionic and zwitterionic phospholipid vesicles. No ionophoric activity was observed for squalamine in vesicles comprised of phosphatidylglycerol (PG), phosphatidylcholine (PC), or a mixture of the two lipids. Experiments using radiolabeled squalamine indicated that all of the squalamine added to PG vesicles remained with the vesicles, while approximately one-half of the squalamine added to PC vesicles was incorporated. We have synthesized the aminosterol analog of squalamine possessing ionophoric activity, and its ionophoric activity in PG vesicles was confirmed. The synthetic compound possessed no measurable lytic activity when added to preformed phospholipid vesicles. As both compounds possess significant antimicrobial activity, these results suggest that either multiple mechanisms for the antimicrobial activity of aminosterols exist, depending upon the aminosterol structure, or possibly an unrelated common mechanism for antimicrobial activity remains to be discovered.
Michael A White - One of the best experts on this subject based on the ideXlab platform.
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The Estrogen-Related Receptor α Inverse Agonist XCT 790 Is a
2016Co-Authors: Nanomolar Mitochondrial Uncoupler, Banu Eskiocak, Aktar Ali, Michael A WhiteAbstract:ABSTRACT: XCT 790 is widely used to inhibit estrogen-related receptor α (ERRα) activity as an inverse agonist. Here, we report that XCT 790 potently activates AMP kinase (AMPK) in a dose-dependent and ERRα-independent manner, with active concentrations more than 25-fold below those typically used to perturb ERRα. AMPK activation is secondary to inhibition of energy production as XCT 790 rapidly depletes the pool of cellular ATP. A concomitant increase in oxygen consumption rates suggests uncoupling of the mitochondrial electron transport chain. Consistent with this, XCT 790 decreased mitochondrial membrane potential without affecting mitochondrial mass. Therefore, XCT 790 is a potent, fast-acting, mitochondrial uncoupler independent of its inhibition of ERRα. The biological activity together with structural features in common with the chemical uncouplers FCCP and CCCP indicates likely mode of action as a Proton Ionophore. The development of cell-permeable synthetic chemicalcompounds that directly and specifically antagonize or agonize a biological entity of interest has been hugely beneficial as they have become tools for probing the mechanism of action of small molecules, proteins, and organelles. These chemical probes (also known as tool compounds) are commonly employed in dynamic perturbation contexts that cannot be mimicked genetically, to modulate both the timing and th
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the estrogen related receptor α inverse agonist xct 790 is a nanomolar mitochondrial uncoupler
Biochemistry, 2014Co-Authors: Banu Eskiocak, Aktar Ali, Michael A WhiteAbstract:XCT 790 is widely used to inhibit estrogen-related receptor α (ERRα) activity as an inverse agonist. Here, we report that XCT 790 potently activates AMP kinase (AMPK) in a dose-dependent and ERRα-independent manner, with active concentrations more than 25-fold below those typically used to perturb ERRα. AMPK activation is secondary to inhibition of energy production as XCT 790 rapidly depletes the pool of cellular ATP. A concomitant increase in oxygen consumption rates suggests uncoupling of the mitochondrial electron transport chain. Consistent with this, XCT 790 decreased mitochondrial membrane potential without affecting mitochondrial mass. Therefore, XCT 790 is a potent, fast-acting, mitochondrial uncoupler independent of its inhibition of ERRα. The biological activity together with structural features in common with the chemical uncouplers FCCP and CCCP indicates likely mode of action as a Proton Ionophore.
Gabriella Spengler - One of the best experts on this subject based on the ideXlab platform.
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genetic response of salmonella enterica serotype enteritidis to thioridazine rendering the organism resistant to the agent
International Journal of Antimicrobial Agents, 2012Co-Authors: Gabriella Spengler, Liliana Rodrigues, Ana Martins, Marta Martins, Matthew P Mccusker, Pedro Cerca, Lisa Machado, S S Costa, Eleni NtokouAbstract:Thioridazine (TZ)-induced accumulation of the universal efflux pump substrate ethidium bromide and its subsequent efflux by Salmonella strains with various degrees of overexpressed efflux pumps takes place automatically at pH 7.4, is independent of a metabolic source, is not affected by a Proton Ionophore and is precluded by palmitic acid. Salmonella enterica serotype Enteritidis cultured in medium containing increasing concentrations of TZ does not grow during the first 6-8h, after which time its growth is similar to unexposed controls. At the end of a 16-h exposure period, the organism is resistant to >250mg/L TZ. Parallel assessment by real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) of the activity of genes that regulate and code for the AcrB transporter of the main efflux pump (AcrAB) of the organism at periodic intervals suggests a sequence of activation beginning with the stress gene soxS, followed by the global regulator ramA, then by the local regulator marA and then by the transporter acrB. These activations take place during the period of no growth. By the end of a 16-h culture period, only the acrB transporter gene is still highly overexpressed. Assessment of the activity of genes of the two-component regulon PmrA/B indicates that TZ also activates this regulon. Because activation of pmrA/B also activates acrB, development of high resistance to TZ during a 16-h culture period is in part due to activation of the two-component regulon.
Barry S. Selinsky - One of the best experts on this subject based on the ideXlab platform.
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squalamine is not a Proton Ionophore
Biochimica et Biophysica Acta, 2000Co-Authors: Barry S. Selinsky, Andrea Frangiosi, Beth Vonbaur, Rob Smith, Larry PedersenAbstract:Abstract Squalamine, an aminosterol antibiotic isolated from the dogfish shark, creates relatively large defects in phospholipid bilayers, allowing the unrestricted translocation of small molecules across these compromised membranes (B.S. Selinsky, Z. Zhou, K.G. Fotjik, S.R. Jones, N.R. Dollahon, A.E. Shinnar, Biochim. Biophys. Acta 1370 (1998) 218–234). However, an aminosterol structurally similar to squalamine was found to act as a Proton Ionophore in anionic phospholipid vesicles. In contrast with squalamine, gross membrane disruption was not observed with this synthetic analog (G. Deng, T. Dewa, S.L. Regen, J. Am. Chem. Soc. 118 (1996) 8975–8976). In this report, the ionophoric activity of squalamine was tested in anionic and zwitterionic phospholipid vesicles. No ionophoric activity was observed for squalamine in vesicles comprised of phosphatidylglycerol (PG), phosphatidylcholine (PC), or a mixture of the two lipids. Experiments using radiolabeled squalamine indicated that all of the squalamine added to PG vesicles remained with the vesicles, while approximately one-half of the squalamine added to PC vesicles was incorporated. We have synthesized the aminosterol analog of squalamine possessing ionophoric activity, and its ionophoric activity in PG vesicles was confirmed. The synthetic compound possessed no measurable lytic activity when added to preformed phospholipid vesicles. As both compounds possess significant antimicrobial activity, these results suggest that either multiple mechanisms for the antimicrobial activity of aminosterols exist, depending upon the aminosterol structure, or possibly an unrelated common mechanism for antimicrobial activity remains to be discovered.
Richard A Proctor - One of the best experts on this subject based on the ideXlab platform.
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transposon disruption of the complex i nadh oxidoreductase gene snod in staphylococcus aureus is associated with reduced susceptibility to the microbicidal activity of thrombin induced platelet microbicidal protein 1
Journal of Bacteriology, 2006Co-Authors: Arnold S Bayer, Peter J Mcnamara, Michael R Yeaman, Natalie Lucindo, Tiffanny Jones, Ambrose L Cheung, Hansgeorg Sahl, Richard A ProctorAbstract:The cationic molecule thrombin-induced platelet microbicidal protein 1 (tPMP-1) exerts potent activity against Staphylococcus aureus. We previously reported that a Tn551 S. aureus transposon mutant, ISP479R, and two bacteriophage back-transductants, TxA and TxB, exhibit reduced in vitro susceptibility to tPMP-1 (tPMP-1(r)) compared to the parental strain, ISP479C (V. Dhawan, M. R. Yeaman, A. L. Cheung, E. Kim, P. M. Sullam, and A. S. Bayer, Infect. Immun. 65:3293-3299, 1997). In the current study, the genetic basis for tPMP-1(r) in these mutants was identified. GenBank homology searches using sequence corresponding to chromosomal DNA flanking Tn551 mutant strains showed that the fourth gene in the staphylococcal mnh operon (mnhABCDEFG) was insertionally inactivated. This operon was previously reported to encode a Na(+)/H(+) antiporter involved in pH tolerance and halotolerance. However, the capacity of ISP479R to grow at pH extremes and in high NaCl concentrations (1 to 3 M), coupled with its loss of transmembrane potential (DeltaPsi) during postexponential growth, suggested that the mnh gene products are not functioning as a secondary (i.e., passive) Na(+)/H(+) antiporter. Moreover, we identified protein homologies between mnhD and the nuo genes of Escherichia coli that encode components of a complex I NADH:ubiquinone oxidoreductase. Consistent with these data, exposures of tPMP-1-susceptible (tPMP-1(s)) parental strains (both clinical and laboratory derived) with either CCCP (a Proton Ionophore which collapses the Proton motive force) or pieracidin A (a specific complex I enzyme inhibitor) significantly reduced tPMP-induced killing to levels seen in the tPMP-1(r) mutants. To reflect the energization of the gene products encoded by the mnh operon, we have renamed the locus sno (S. aureus nuo orthologue). These novel findings indicate that disruption of a complex I enzyme locus can confer reduced in vitro susceptibility to tPMP-1 in S. aureus.
