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Peter J. O'hanlon - One of the best experts on this subject based on the ideXlab platform.
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The Chemistry of Pseudomonic Acid. Part 13. Modifications at C-12 to C- 14.
ChemInform, 2010Co-Authors: Andrew Keith Forrest, Peter J. O'hanlon, Graham WalkerAbstract:Abstract The novel antibiotic, Pseudomonic Acid, binds tightly to its target enzyme, isoleucyl t-RNA synthetase. The C12 to C14 region of the molecule is thought to bind to the isoleucine binding site of the enzyme. Semisynthetic analogues in which functionality present in this region have been systematically modified are reported here: all the derivatives prepared showed weak enzyme binding.
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Synthesis and Antibacterial Properties of β‐Diketone Acrylate Bioisosteres of Pseudomonic Acid A.
ChemInform, 2010Co-Authors: Isobel Bennett, Nigel J. P. Broom, John Stephen Elder, Robert Cassels, Nicky D. Masson, Peter J. O'hanlonAbstract:Abstract A series of β-diketone acrylate bioisosteres 4 of Pseudomonic Acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents. A number of analogues have excellent antibacterial activity. Selected examples were show to afford good blood levels and to be effective in a murine infection model.
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Rational design of femtomolar inhibitors of isoleucyl tRNA synthetase from a binding model for Pseudomonic Acid-A.
Biochemistry, 2000Co-Authors: Murray J. B. Brown, Peter J. O'hanlon, Nigel J. P. Broom, Andrew Keith Forrest, Lucy Mensah, Michael Doyle, Neal Osbourne, Christine M. Richardson, Andrew J. PopeAbstract:This paper describes the design and characterization of novel inhibitors of IleRS, whose binding affinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from a binding model for the natural product Pseudomonic Acid-A (PS-A) together with a detailed understanding of the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediate IleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylation of tRNA or PP(i)/ATP exchange at supersaturating substrate concentration and by transient kinetics and calorimetry methods. A detailed understanding of the interaction of a comprehensive series of compounds with IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors. Predictions based on these results have been recently supported by a docking model based on the crystal structure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].
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A versatile approach to the total synthesis of the Pseudomonic Acids
Chemical Communications, 2000Co-Authors: Catherine Mckay, Thomas J Simpson, Andrew Keith Forrest, Christine L. Willis, Peter J. O'hanlonAbstract:The total synthesis of Pseudomonic Acid C is described using an approach which gives access to analogues and putative biosynthetic precursors; the key step is installation of the C7 side-chain via alkylation of a trisubstituted δ-lactone with complete stereocontrol and in 85% yield under conditions which avoid the possible competing elimination of a protected hydroxy group β to the carbonyl.
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Synthesis and antibacterial properties of β-diketone acrylate bioisosteres of Pseudomonic Acid A
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Isobel Bennett, Nigel J. P. Broom, John Stephen Elder, Robert Cassels, Nicky D. Masson, Peter J. O'hanlonAbstract:Abstract A series of β-diketone acrylate bioisosteres 4 of Pseudomonic Acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents. A number of analogues have excellent antibacterial activity. Selected examples were show to afford good blood levels and to be effective in a murine infection model.
Nigel J. P. Broom - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Antibacterial Properties of β‐Diketone Acrylate Bioisosteres of Pseudomonic Acid A.
ChemInform, 2010Co-Authors: Isobel Bennett, Nigel J. P. Broom, John Stephen Elder, Robert Cassels, Nicky D. Masson, Peter J. O'hanlonAbstract:Abstract A series of β-diketone acrylate bioisosteres 4 of Pseudomonic Acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents. A number of analogues have excellent antibacterial activity. Selected examples were show to afford good blood levels and to be effective in a murine infection model.
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Rational design of femtomolar inhibitors of isoleucyl tRNA synthetase from a binding model for Pseudomonic Acid-A.
Biochemistry, 2000Co-Authors: Murray J. B. Brown, Peter J. O'hanlon, Nigel J. P. Broom, Andrew Keith Forrest, Lucy Mensah, Michael Doyle, Neal Osbourne, Christine M. Richardson, Andrew J. PopeAbstract:This paper describes the design and characterization of novel inhibitors of IleRS, whose binding affinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from a binding model for the natural product Pseudomonic Acid-A (PS-A) together with a detailed understanding of the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediate IleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylation of tRNA or PP(i)/ATP exchange at supersaturating substrate concentration and by transient kinetics and calorimetry methods. A detailed understanding of the interaction of a comprehensive series of compounds with IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors. Predictions based on these results have been recently supported by a docking model based on the crystal structure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].
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Synthesis and antibacterial properties of β-diketone acrylate bioisosteres of Pseudomonic Acid A
Bioorganic & medicinal chemistry letters, 1999Co-Authors: Isobel Bennett, Nigel J. P. Broom, John Stephen Elder, Robert Cassels, Nicky D. Masson, Peter J. O'hanlonAbstract:Abstract A series of β-diketone acrylate bioisosteres 4 of Pseudomonic Acid A 1 have been synthesized and evaluated for their ability to inhibit bacterial isoleucyl-tRNA synthetase and act as antibacterial agents. A number of analogues have excellent antibacterial activity. Selected examples were show to afford good blood levels and to be effective in a murine infection model.
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characterization of isoleucyl trna synthetase from staphylococcus aureus ii mechanism of inhibition by reaction intermediate and Pseudomonic Acid analogues studied using transient and steady state kinetics
Journal of Biological Chemistry, 1998Co-Authors: Andrew J. Pope, Nigel J. P. Broom, Murray J. B. Brown, Lucy Mensah, Neal Osbourne, Keith J Moore, Mary Mcvey, Neil Benson, Peter J OhanlonAbstract:The interactions of isoleucyl-tRNA synthetase (IleRS, E) from Staphylococcus aureus with both intermediate analogues and Pseudomonic Acid (PS-A) have been investigated using transient and steady-state techniques. Non-hydrolyzable analogues of isoleucyl-AMP (I) were simple competitive inhibitors (Ile-ol-AMP, Ki = 50 nM and Ile-NHSO2-AMP, Ki = 1 nM;). PS-A (J) inhibits IleRS via a slow-tight binding competitive mechanism where E.J (Kj = approximately 2 nM), undergoes an isomerization to form a stabilized E*.J complex (K*j = 50 pM). To overcome tight-binding artifacts when K*j > Km, thus raising K*j,app well above [E]. Using [3H]PS-A, it was confirmed that binding occurs with 1:1 stoichiometry and is reversible. Formation of inhibitor complexes was monitored directly through changes in enzyme tryptophan fluorescence. For Ile-ol-AMP and Ile-NHSO2-AMP, the fluorescence intensity of E.I was identical to that when E.Ile-AMP forms catalytically. Binding of PS-A induced only a small change in IleRS fluorescence that was characterized using transient kinetic competition. SB-205952, a PS-A analogue, produced a 37% quenching of IleRS fluorescence upon binding as a result of radiationless energy transfer. Inhibitor reversal rates were obtained by measuring relaxation between spectroscopically different complexes. Together, these data represent a comprehensive solution to the kinetics of inhibition by these compounds.
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the chemistry of Pseudomonic Acid 18 heterocyclic replacement of the α β unsaturated ester synthesis molecular modeling and antibacterial activity1
Journal of Medicinal Chemistry, 1997Co-Authors: Pamela Brown, Nigel J. P. Broom, Robert Cassels, Desmond John Best, Peter J Ohanlon, Timothy Mitchell, Neal Frederick Osborne, Jennifer M. WilsonAbstract:The electronic requirements around the C1-C3 region of Pseudomonic Acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.
Jennifer M. Wilson - One of the best experts on this subject based on the ideXlab platform.
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the chemistry of Pseudomonic Acid 18 heterocyclic replacement of the α β unsaturated ester synthesis molecular modeling and antibacterial activity1
Journal of Medicinal Chemistry, 1997Co-Authors: Pamela Brown, Nigel J. P. Broom, Robert Cassels, Desmond John Best, Peter J Ohanlon, Timothy Mitchell, Neal Frederick Osborne, Jennifer M. WilsonAbstract:The electronic requirements around the C1-C3 region of Pseudomonic Acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.
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The Chemistry of Pseudomonic Acid.† 18. Heterocyclic Replacement of the α,β-Unsaturated Ester: Synthesis, Molecular Modeling, and Antibacterial Activity1
Journal of medicinal chemistry, 1997Co-Authors: Pamela Brown, Peter J. O'hanlon, Nigel J. P. Broom, Robert Cassels, Desmond John Best, Neal Frederick Osborne, Timothy J. Mitchell, Jennifer M. WilsonAbstract:The electronic requirements around the C1-C3 region of Pseudomonic Acid analogues were investigated. Synthetic routes were developed to access a range of compounds where the alpha, beta-unsaturated ester moiety had been replaced by a 5-membered ring heterocycle. The inhibition of isoleucyl tRNA synthetase from Staphylococcus aureus NCTC 6571 was determined as was the minimum inhibitory concentration (MIC) of the test compounds against that organism. Compounds possessing a region of electrostatic potential corresponding to that of the carbonyl group in the alpha, beta-unsaturated ester, and a low-energy unoccupied molecular orbital in the region corresponding to the double bond, were found to have IC50 values of 0.7-5.3 ng mL-1. However the MIC values of these compounds were in the range 2.0-8.0 micrograms mL-1, reflecting their poorer penetration into the bacterial cell.
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The Chemistry of Pseudomonic Acid. 17. Dual-Action C-1 Oxazole Derivatives of Pseudomonic Acid Having an Extended Spectrum of Antibacterial Activity†
Journal of medicinal chemistry, 1996Co-Authors: Nigel J. P. Broom, Peter J. O'hanlon, John Stephen Elder, Robert Cassels, ∇ Hung-yuan Cheng, Peter C. T. Hannan, Nicki Masson, And Andrew Pope, Jennifer M. WilsonAbstract:A series of C-1 oxazole isosteres of Pseudomonic Acid A (mupirocin) bearing a nitroheterocycle have been synthesized, and significant differences in both spectrum of activity and potency were found between these derivatives and mupirocin. Additionally, the antibacterial potency of two members of this class of compounds against mupirocin-resistant staphylococci could not be accounted for solely by inhibition of the target enzyme isoleucyl-tRNA synthetase (IRS), indicating an additional mode of action. The most potent compound, the nitrofuran 3f (SB 205952), was the most electron affinic derivative prepared and was transformed by NAD(P)H-dependent bacterial reductases at a rate similar to that for nitrofurantoin. The second mode of action of this compound may therefore arise from its reduction to a species with cellular targets other than IRS. In in vivo studies, 3f was shown to be a very effective agent by both the subcutaneous and oral routes of administration.
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The chemistry of Pseudomonic Acid. Part 14. Synthesis and in vivo biological activity of heterocyclyl substituted oxazole derivatives.
The Journal of antibiotics, 1995Co-Authors: Nigel J. P. Broom, Peter J. O'hanlon, John Stephen Elder, Peter Charles Thomas Hannan, J. E. Pons, Graham Walker, Jennifer M. Wilson, P. WoodallAbstract:Semisynthetic analogues of Pseudomonic Acid A have been prepared containing a heterocyclyl substituted oxazole. Derivatives in which the heterocycle was thiophene, furan, pyridine, or isoxazole showed good antibacterial potency and were further evaluated in vivo. Both pharmacokinetic parameters and oral activity against an experimental intraperitoneal sepsis were superior to results obtained from previously described Pseudomonic Acid A derivatives.
Pabbaraja Srihari - One of the best experts on this subject based on the ideXlab platform.
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A unified strategy for the synthesis of the C1–C14 fragment of marinolic Acids, mupirocins, Pseudomonic Acids and thiomarinols: total synthesis of Pseudomonic Acid methyl monate C
Organic and Biomolecular Chemistry, 2014Co-Authors: Y. Sridhar, Pabbaraja SrihariAbstract:A flexible stereoselective approach to the common C1–C14 skeleton present in natural products of the Pseudomonic Acid family is described. The strategy has been extended and the total synthesis of Pseudomonic Acid methyl monate C was achieved. The key synthetic reactions utilized include Achmatowicz rearrangement, Johnson–Claisen rearrangement, Julia–Kocienski olefination, and Horner–Wadsworth–Emmons olefination reaction.
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A unified strategy for the synthesis of the C1-C14 fragment of marinolic Acids, mupirocins, Pseudomonic Acids and thiomarinols: total synthesis of Pseudomonic Acid methyl monate C.
Organic & biomolecular chemistry, 2014Co-Authors: Y. Sridhar, Pabbaraja SrihariAbstract:A flexible stereoselective approach to the common C1–C14 skeleton present in natural products of the Pseudomonic Acid family is described. The strategy has been extended and the total synthesis of Pseudomonic Acid methyl monate C was achieved. The key synthetic reactions utilized include Achmatowicz rearrangement, Johnson–Claisen rearrangement, Julia–Kocienski olefination, and Horner–Wadsworth–Emmons olefination reaction.
Thomas Leisinger - One of the best experts on this subject based on the ideXlab platform.
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Transcription of the ileS operon in the archaeon Methanobacterium thermoautotrophicum Marburg.
Journal of bacteriology, 1993Co-Authors: Urs Jenal, C Thurner, Thomas LeisingerAbstract:In the thermophilic archaeon Methanobacterium thermoautotrophicum Marburg, the structural gene for isoleucyl-tRNA synthetase (ileS) is flanked upstream by orf401 and downstream by purL. orf401 encodes a 43.5-kDa protein with an unknown function. Northern (RNA) hybridization and S1 nuclease protection experiments showed that the orf401, ileS, and purL genes are cotranscribed from an archael consensus promoter in front of orf401. The corresponding transcript was about eightfold increased in cells that had been exposed to Pseudomonic Acid A, a specific inhibitor of isoleucyl-tRNA synthetase. Growth inhibition by puromycin, tryptophan starvation, or starvation for hydrogen did not affect the level of this transcript. The level of a trpE transcript, however, was drastically elevated upon tryptophan starvation, while inhibition by Pseudomonic Acid A had no effect on the level of this transcript. Expression of ileS thus appears to be controlled by a regulatory mechanism which specifically responds to the availability of isoleucyl-tRNA. Extensive decay of the orf401-ileS-purL message was observed. Degradation occurred, presumably by endonucleolytic cleavage, within the orf401 region.
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Isoleucyl-tRNA synthetase of Methanobacterium thermoautotrophicum Marburg. Cloning of the gene, nucleotide sequence, and localization of a base change conferring resistance to Pseudomonic Acid.
The Journal of biological chemistry, 1991Co-Authors: Urs Jenal, Thomas Rechsteiner, Pei-ying Tan, E. Buhlmann, Leo Meile, Thomas LeisingerAbstract:The ileS gene encoding the isoleucyl-tRNA synthetase of the thermophilic archaebacterium Methanobacterium thermoautotrophicum Marburg was isolated and sequenced. ileS was closely flanked by an unknown open reading frame and by purL and thus is arranged differently from the organizations observed in several eubacteria or in Saccharomyces cerevisiae. The deduced amino Acid sequence of isoleucyl-tRNA synthetase was compared with primary sequences of isoleucyl-, valyl-, leucyl-, and methionyl-tRNA synthetases from eubacteria and yeast. The archaebacterial enzyme fitted well into this group of enzymes. It contained the two short consensus sequences observed in class I aminoacyl-tRNA synthetases as well as regions of homology with enzymes of the isoleucine family. Comparison between the isoleucyl-tRNA synthetases of M. thermoautotrophicum yielded 36% amino Acid identity with the yeast enzyme and 32% identity with the corresponding enzyme from Escherichia coli. The ileS gene of the Pseudomonic Acid-resistant M. thermoautotrophicum mutant MBT10 was also sequenced. The mutant enzyme had undergone a glycine to aspartic Acid transition at position 590, in a conserved region comprising the KMSKS consensus sequence. The inhibition constants of Pseudomonic Acid, KiIle and KiATP, for the mutant enzyme were 10-fold higher than those determined for the wild-type enzyme. Both the mutant and the wild-type ileS gene were expressed in E. coli, and their products displayed the expected difference in sensitivity toward Pseudomonic Acid.
