- One step preparation and electrochemical analysis of IQS, a cell-cell communication signal in the nosocomial pathogen Pseudomonas aeruginosa
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Pseudomonas aeruginosa uses a hierarchical cell-cell communication system consisting of a number of regulatory elements to coordinate the expression of bacterial virulence genes. Sensitive detection of quorum sensing (QS) molecules has the potential for early identification of P. aeruginosa facilitating early medical intervention. A recently isolated cell-cell communication molecule, a thiazole termed IQS, can bypass the las QS system of P. aeruginosa under times of stress, activating a subset of QS-controlled genes. This compound offers a new target for pathogen detection and has been prepared in a one step protocol. A simple electrochemical strategy was employed for its sensitive detection using boron-doped diamond and glassy carbon electrodes by cyclic voltammetry and amperometry.
- Shang, Fengjun,Muimhneacháin, Eoin ó,Jerry Reen,Buzid, Alyah,O'Gara, Fergal,Luong, John H.T.,Glennon, Jeremy D.,McGlacken, Gerard P.
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- Stuffed Methyltransferase Catalyzes the Penultimate Step of Pyochelin Biosynthesis
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Nonribosomal peptide synthetases use tailoring domains to incorporate chemical diversity into the final natural product. A structurally unique set of tailoring domains are found to be stuffed within adenylation domains and have only recently begun to be characterized. PchF is the NRPS termination module in pyochelin biosynthesis and includes a stuffed methyltransferase domain responsible for S-adenosylmethionine (AdoMet)-dependent N-methylation. Recent studies of stuffed methyltransferase domains propose a model in which methylation occurs on amino acids after adenylation and thiolation rather than after condensation to the nascent peptide chain. Herein, we characterize the adenylation and stuffed methyltransferase didomain of PchF through the synthesis and use of substrate analogues, steady-state kinetics, and onium chalcogen effects. We provide evidence that methylation occurs through an SN2 reaction after thiolation, condensation, cyclization, and reduction of the module substrate cysteine and is the penultimate step in pyochelin biosynthesis.
- Ronnebaum, Trey A.,McFarlane, Jeffrey S.,Prisinzano, Thomas E.,Booker, Squire J.,Lamb, Audrey L.
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- Pyochelin Biosynthetic Metabolites Bind Iron and Promote Growth in Pseudomonads Demonstrating Siderophore-like Activity
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Pseudomonads employ several strategies to sequester iron vital for their survival including the use of siderophores such as pyoverdine and pyochelin. Similar in structure but significantly less studied are pyochelin biosynthetic byproducts, dihydroaeruginoic acid, aeruginoic acid, aeruginaldehyde (IQS), and aeruginol, along with two other structurally related molecules, aerugine and pyonitrins A-D, which have all been isolated from numerous Pseudomonad extracts. Because of the analogous substructure of these compounds to pyochelin, we hypothesized that they may play a role in iron homeostasis or have a biological effect on other bacterial species. Herein, we discuss the physiochemical evaluation of these molecules and disclose, for the first time, their ability to bind iron and promote growth in Pseudomonads.
- Kaplan, Anna R.,Musaev, Djamaladdin G.,Wuest, William M.
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p. 544 - 551
(2021/03/03)
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- Synthesis and Investigation of the Abiotic Formation of Pyonitrins A-D
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Pyonitrins A-D are recently isolated natural products from the insect-associated Pseudomonas protegens strain, which were isolated from complex fractions that exhibited antifungal activity via an in vivo murine candidiasis assay. Genomic studies of Pseudomonas protegens suggested that pyonitrins A-D are formed via a spontaneous nonenzymatic reaction between biosynthetic intermediates of two well-known natural products pyochelin and pyrrolnitrin. Herein we have accomplished the first biomimetic total synthesis of pyonitrins A-D in three steps and studied the nonenzymatic formation of the pyonitrins using 15N NMR spectroscopy.
- Aniebok, Victor,Lee, Hsiau-Wei,Macmillan, John B.,Shingare, Rahul D.
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- Thiazolidine derivatives as potent and selective inhibitors of the PIM kinase family
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The PIM family of serine/threonine kinases have become an attractive target for anti-cancer drug development, particularly for certain hematological malignancies. Here, we describe the discovery of a series of inhibitors of the PIM kinase family using a high throughput screening strategy. Through a combination of molecular modeling and optimization studies, the intrinsic potencies and molecular properties of this series of compounds was significantly improved. An excellent pan-PIM isoform inhibition profile was observed across the series, while optimized examples show good selectivity over other kinases. Two PIM-expressing leukemic cancer cell lines, MV4-11 and K562, were employed to evaluate the in vitro anti-proliferative effects of selected inhibitors. Encouraging activities were observed for many examples, with the best example (44) giving an IC50 of 0.75 μM against the K562 cell line. These data provide a promising starting point for further development of this series as a new cancer therapy through PIM kinase inhibition.
- Bataille, Carole J.R.,Brennan, Méabh B.,Byrne, Simon,Davies, Stephen G.,Durbin, Matthew,Fedorov, Oleg,Huber, Kilian V.M.,Jones, Alan M.,Knapp, Stefan,Liu, Gu,Nadali, Anna,Quevedo, Camilo E.,Russell, Angela J.,Walker, Roderick G.,Westwood, Robert,Wynne, Graham M.
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supporting information
p. 2657 - 2665
(2017/04/06)
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- Synthesis of new thiazole analogues of pyochelin, a siderophore of Pseudomonas aeruginosa and Burkholderia cepacia. A new conversion of thiazolines into thiazoles
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Three pyochelin analogues and their methyl esters all containing a thiazole ring have been synthesised from the same Weinreb amide key intermediate. One of these analogues called HPTT-COOH, a molecule released in the course of pyochelin and yersiniabactin biosynthesis, was efficiently synthesised using a new base induced conversion of the key compound 2′-(2-hydroxyphenyl)- 2′-thiazoline-4′-(N-methoxy,N-methyl) carboxamide into 2′-(2-hydroxyphenyl)-2′-thiazole-4′-(N-methoxy,N-methyl) carboxamide. Graphical Abstract
- Mislin, Ga?tan L.,Burger, Alain,Abdallah, Mohamed A.
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p. 12139 - 12145
(2007/10/03)
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- An improved stereocontrolled synthesis of pyochelin, siderophore of Pseudomonas aeruginosa and Burkholderia cepacia
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A considerably improved stereocontrolled synthesis of pyochelin, a hydroxyphenylthiazolinylthiazolidine type of siderophore common to most strains of Pseudomonas aeruginosa and Burkholderia cepacia is described. 2'- (2-Hydroxyphenyl)-2'-thiazoline-4'-carboxaldehyde, a key molecule involved in this synthesis has been prepared by reduction of 2'-(2-hydroxyphenyl)-2'- thiazoline-4'-(N-methoxy,N-methyl) carboxamide with lithium aluminium hydride. The aldehyde was further coupled with (R)-N-methylcysteine to yield pyochelin. Under the conditions reported, epimerization at the C-4' center was considerably diminished.
- Zamri, Adel,Abdallah, Mohamed A.
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p. 249 - 256
(2007/10/03)
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- The constitution and properties of a pyochelin-zinc complex
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The siderophore pyochelin, identified for the first time as a metabolite of Pseudomonas fluorescens, was isolated in highly pure form as a dimeric complex with two zinc atoms.The (1)H and (13)C magnetic resonance data for the two pyochelin moieties of the complex differ significantly from each other and from those of free pyochelin.The complex also exhibits unusual solubility and stability properties.Since it is easily isolable and can be readily converted into highly pure, free pyochelin, it offers an excellent entry to further biological studies on this important metabolite.
- Cuppels, Diane A.,Stipanovic, Robert D.,Stoessl, Albert,Stothers, J. B.
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p. 2126 - 2130
(2007/10/02)
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- 2-Phenylthiazole Derivatives from Pseudomonas cepacia
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From the culture medium of Pseudomonas cepacia 2-(o-hydroxyphenyl)-thiazol and its 4-carbaldehyd and 4-carboxylic acid derivatives (aeruginoic acid) could be isolated.Their structures were elucidated and confirmed by synthesis. - Key words: Phenylthiazols, Bacterial Metabolites, Pseudomonas cepacia, Mass Spectra
- Bukovits, G. J.,Mohr, N.,Budzikiewicz, H.,Korth, H.,Pulverer, G.
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p. 877 - 880
(2007/10/02)
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