Spelling suggestions: "subject:"siderophore."" "subject:"siderophores.""
1 |
Towards the synthesis of new macrocyclic receptorsBukhari, Abeer January 2017 (has links)
Iron plays a fundamental role in the regulation of chemical processes within biological systems and the control of intracellular iron concentration has important consequences in the aetiology of a variety of disease states (e.g. neurodegenerative disorders). In this thesis, which is concerned with the identification of new macrocyclic receptors, the synthesis of (N,N',N''-((3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl)tris(2,3-dihydroxybenzenesulfonamide), a mimic to the natural siderophore enterochelin, is reported. Two synthetic routes to the preparation of this macrocycle are presented where a sulfonamide residue is attached to a functionalised lactone core. The title compound was prepared either via the cyclotrimerzation of methyl N-((2,3-dimethoxyphenyl)sulfonyl)-L-serinate (âpre-functionalizationâ method) or by the elaboration of a preformed macrocyclic scaffold, (3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triaminium chloride, with 2,3-dimethoxybenzenesulfonyl chloride (âpost-functionalizationâ method). Late-stage demethylation of the macrocyle formed in these reactions - N,Nâ,Nââ-((3S,7S,11S)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7,11-triyl)tris(2,3-dimethoxybenzenesulfonamide) using BBr3 afforded the desired enterochelin analogue. These studies indicated that the âpost-functionalisationâ protocol afforded higher yields of the desired macrocycle in a process which was not marred by the concomitant formation of sulphonamide by-products. During the synthesis of 2,3-diacetoxy-5,6-dimethylsulfonyl chloride, a key intermediate for the assembly of functionalised sulphonamide siderophores, an ortho-quinone intermediate was found to undergo an intermolecular Diels-Alder reaction from which both the keto- ((1S*,4S*,4aR*,8aS*)-2,3,8,8a-tetramethyl-1,4,4a,8a-tetrahydro-1,4-ethanonaphthalene-5,6,9,10-tetraone) and enol- ((1S*,4R*,8aS*)-5-hydroxy-2,3,8,8a-tetramethyl-1,8a-dihydro-1,4-ethanonaphthalene-6,9,10(4H)-trione) tautomeric forms could be isolated and fully characterised by X-ray crystallography thereby constituting a rare example of desmotropy.
|
2 |
Probing linker design in citric acid-ciprofloxacin conjugatesMilner, S.J., Snelling, Anna M., Kerr, Kevin G., Abd-El-Aziz, A., Thomas, G.H., Hubbard, R.E., Routledge, A., Duhme-Klair, A-K. January 2014 (has links)
No / A series of structurally related citric acid-ciprofloxacin conjugates was synthesised to investigate the influence of the linker between citric acid and ciprofloxacin on antibacterial activities. Minimum inhibitory concentrations (MICs) were determined against a panel of reference strains and clinical isolates of bacteria associated with infection in humans and correlated with the DNA gyrase inhibitory activity. The observed trend was rationalised by computational modelling.
|
3 |
Iron acquisition in <i> Acinetobacter baumannii </i>Penwell, William Frank 23 April 2013 (has links)
No description available.
|
4 |
Protection Against Myocardial Ischemia/Reperfusion Injury in tlr4-Deficient Mice Is Mediated Through a Phosmolecular Mechanism of Ferricsiderophore Passage Through the Outer Membrane Receptor Proteins of Escherichia Coliphoinositide 3-Kinase-Dependent MechanismChakraborty, Ranjan, Storey, Erin, Van Der Helm, Dick 01 June 2007 (has links)
Iron is an essential nutrient for all microorganisms with a few exceptions. Microorganisms use a variety of systems to acquire iron from the surrounding environment. One such system includes production of an organic molecule known as a siderophore by many bacteria and fungi. Siderophores have the capacity to specifically chelate ferric ions. The ferricsiderophore complex is then transported into the cell via a specific receptor protein located in the outer membrane. This is an energy dependent process and is the subject of investigation in many research laboratories. The crystal structures of three outer membrane ferricsiderophore receptor proteins FepA, FhuA and FecA from Escherichia coli and two FpvA and FptA from Pseudomonas aeruginosa have recently been solved. Four of them, FhuA, FecA, FpvA and FptA have been solved in ligand-bound forms, which gave insight into the residues involved in ligand binding. The structures are similar and show the presence of similar domains; for example, all of them consist of a 22 strand-β-barrel formed by approximately 600 C-terminal residues while approximately 150 N-terminal residues fold inside the barrel to form a plug domain. The plug domain obstructs the passage through the barrel; therefore our research focuses on the mechanism through which the ferricsiderophore complex is transported across the receptor into the periplasm. There are two possibilities, one in which the plug domain is expelled into the periplasm making way for the ferricsiderophore complex and the second in which the plug domain undergoes structural rearrangement to form a channel through which the complex slides into the periplasm. Multiple alignment studies involving protein sequences of a large number of outer membrane receptor proteins that transport ferricsiderophores have identified several conserved residues. All of the conserved residues are located within the plug and barrel domain below the ligand binding site. We have substituted a number of these residues in FepA and FhuA with either alanine or glutamine resulting in substantial changes in the chemical properties of the residues. This was done to study the effect of the substitutions on the transport of ferricsiderophores. Another strategy used was to create a disulfide bond between the residues located on two adjacent β-strands of the plug domain or between the residues of the plug domain and the β-barrel in FhuA by substituting appropriate residues with cysteine. We have looked for the variants where the transport is affected without altering the binding. The data suggest a distinct role of these residues in the mechanism of transport. Our data also indicate that these transporters share a common mechanism of transport and that the plug remains within the barrel and possibly undergoes rearrangement to form a channel to transport the ferricsiderophore from the binding site to the periplasm.
|
5 |
Iron Acquisition in <em>Rhodococcus erythrolpolis</em>: the Isolation of Mutant(s) that Do Not Produce a Siderophore.Vellore, Jaishree M 01 December 2001 (has links) (PDF)
Rhodococcus, a soil bacterium, displays a diverse range of metabolic capabilities with a number of potential practical applications. To exploit the metabolic potential of Rhodococcus, their basic physiology, genetics, and especially the acquisition of essential nutrients like iron, must be understood.
R. erythropolis strain IGTS8 releases a small compound called a siderophore, that scavenges ferric iron from the environment. To learn more about the genetic control of iron acquisition, mutant(s) defective in siderophore production were isolated. Mutants were generated, by inserting a mutagenic plasmid, pJCS506, into the bacterial cell using electroporation. The plasmid, which cannot replicate in these bacterial cells, randomly inserts into the R. erythropolis genome producing mutations. The potential mutants were detected by screening on a chrome azurol S plate, which detects siderophore production. Colonies that failed to produce siderophore were tested by liquid assays. The strain N5-59 was confirmed as a non-siderophore producing mutant by liquid assays.
|
6 |
Biochemical characterization of Aspergillus fumigatus SidA: a flavin-dependent N-hydroxylating enzymeChocklett, Samuel Wyatt 06 January 2010 (has links)
Ferrichrome is a hydroxamate-containing siderophore produced by the pathogenic fungus Aspergillus fumigatus during infection. This siderophore includes N5-hydroxylated L-ornithine in the peptide backbone that serve as iron chelators. Af SidA is the L-ornithine N5-hydroxylase, which performs the first enzymatic step in the biosynthesis of ferrichrome. In this study, Af SidA was recombinantly expressed and purified as a soluble tetramer with a bound FAD cofactor. The enzyme demonstrated typical Michaelis-Menten kinetics in a product formation assay with respect to L-ornithine, but similar experiments as a function NADH and NADPH indicated inhibition at high coenzyme concentrations. Af SidA is highly specific for its substrate; however, it is promiscuous with respect to its coenzyme requirement. A multi-functional role of NADPH is observed since NADP+ is a competitive inhibitor with respect to NADPH and steady-state kinetic experiments indicate that Af SidA forms a ternary complex with NADP+ and L-ornithine for catalysis. Furthermore, in the absence of substrate, Af SidA forms a stable C4a-(hydro)peroxyflavin intermediate that is stable on the second time scale. Af SidA is also inhibited by several halides and the arginine-reactive reagent, phenylglyoxal. Biochemical comparison of Af SidA to other flavin-containing monooxygenases reveal that Af SidA likely proceeds by a sequential-ordered mechanism. / Master of Science in Life Sciences
|
7 |
Mechanistic Studies and Inhibition of N-hydroxylating MonooxygenasesBufkin, Kendra Bernice 23 May 2017 (has links)
N-hydroxylating monooxygenases (NMO) are members the class B flavoprotein monooxygenases. They catalyze the N-hydroxylation of lysine and ornithine and play and essential role in the biosynthesis of hydroxamate containing siderophores. Siderophores are high affinity iron-chelators composed of catechol and hydroxamate functional groups that are synthesized and secreted by several microorganisms and plants. It has been showed that many NMOs are essential for virulence in many opportunistic pathogens such as Aspergillus fumigatus and Pseudomonas aeruginosa. The focus of my research is on the N-hydroxylating enzymes: Siderophore A (SidA) from Aspergillus fumigatus and Amycolatoposis alba monooxygenase (AMO).
One of my projects is focusing on identifying inhibitors of SidA that will ultimately block the siderophore biosynthesis in A. fumigatus. Out of 973 compounds screened using an activity high-throughput assays two compounds were identified. These were, wortmannin a steroid metabolite and ebselen a benzoselenazole as SidA inhibitors with IC50 values of 369 µM and 11 µM respectively. A second part of this works investigates the hydroxamate formation of the siderophore albachelin in Amycolatoposis alba with the purpose of better understanding this class of enzymes and their catalytic mechanism. The enzyme was purified and characterized in its holo (FAD-bound) and apo (unbound) forms. Pre-steady and steady state kinetics shows that the two forms have different coenzyme preference; apo-AMO prefers NADH while holo-AMO has a higher affinity to NADPH. / Master of Science in Life Sciences
|
8 |
Studies in the Chemistry of Marine Natural ProductsHickford, Sarah Jane Herbison January 2007 (has links)
Compounds from the marine environment exhibit a wide variety of biological activities, and thus hold much promise as potential drugs. The halichondrins, isolated from the Kaikoura sponge Lissodendoryx sp. are no exception to this, demonstrating potent anticancer activity. Novel cytotoxic compounds have also been isolated from the Chatham Rise sponge Lamellomorpha strongylata. Knowledge of the cellular origins of such compounds is desirable, in order to establish if the sponge or associated micro-organisms are producing the compounds of interest. Siderophores are also important molecules, which are produced on demand by bacteria in order to obtain sufficient iron necessary for their growth. Knowledge of the biosynthesis of these compounds has potential for the control of undesirable bacteria, such as the anthrax-causing pathogen Bacillus anthracis. Cell separation studies have been carried out on Lamellomorpha strongylata, locating a swinholide in sponge-associated filamentous bacteria and theonellapeptolides in sponge-associated unicellular bacteria. A microscopic analysis of dissociated cells from Lissodendoryx sp. was also undertaken. The structures of four new halichondrins (3.13 - 3.16), isolated from Lissodendoryx sp., have been determined from spectral data. All of these compounds are very similar to known B series halichondrins, with differences occurring only beyond carbon 44. As biological activity has been shown to be derived from the portion of the molecule between carbons 1 and 35, they all retain good activity in the P388 assay as expected. A new siderophore, petrobactin sulfonate (4.2), was characterised, along with three cyclic imide siderophore derivatives (4.3 - 4.5). Petrobactin sulfonate is the first marine siderophore containing a sulfonated 3,4-dihydroxy aromatic ring. The structures were elucidated from spectral data, resulting in a revision of the NMR assignments of petrobactin.
|
9 |
The Discovery, Isolation, Structure Elucidation and Total Synthesis of the Fuscachelins, Nonribosomal Peptide Siderophores form the Thermophilic Actinomycete <italic>Thermobifida fusca</italic>Dimise, Eric January 2010 (has links)
Thesis advisor: Steven D. Bruner / Thesis advisor: Mary F. Roberts / The fuscachelins are a group of novel small molecule secondary metabolites produced by the thermophilic actinomycete <italic>Thermobifida fusca</italic>. A genome mining approach was employed to identify the fuscachelin nonribosomal peptide synthetase biosynthetic gene cluster in <italic>T. fusca</italic>. The peptide natural products were predicted to be siderophores, iron-scavenging small molecules. An assay guided fractionation approach was utilized to isolate the fuscachelins. Structure elucidation efforts employed nuclear magnetic resonance, mass spectrometric and chemical degradation techniques to determine the structure of the isolated compounds. Once the structure was known, a total synthesis was undertaken. The established synthetic route to the fuscachelins will allow for the facile development of custom-designed chemical tools for the further study of the fuscachelin biosynthetic enzymes and utilization proteins. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.
|
10 |
Avaliação da expressão de um suposto gene responsável pela síntese de sideróforo em mycobacterium massiliense, em diferentes condições de disponibilidade de ferro / Evaluation of the expression of a putative gene responsible for the synthesis of siderophore in Mycobacterium massiliense under different conditions of iron availabilityRocha, V. L. 21 May 2014 (has links)
Submitted by Luanna Matias (lua_matias@yahoo.com.br) on 2015-02-04T16:18:28Z
No. of bitstreams: 2
Dissertação - Viviane Lopes Rocha - 2014.pdf: 3025545 bytes, checksum: 8144fc57a9ecf1ebc51b1286fa161d44 (MD5)
license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-02-05T10:07:09Z (GMT) No. of bitstreams: 2
Dissertação - Viviane Lopes Rocha - 2014.pdf: 3025545 bytes, checksum: 8144fc57a9ecf1ebc51b1286fa161d44 (MD5)
license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-02-05T10:07:09Z (GMT). No. of bitstreams: 2
Dissertação - Viviane Lopes Rocha - 2014.pdf: 3025545 bytes, checksum: 8144fc57a9ecf1ebc51b1286fa161d44 (MD5)
license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)
Previous issue date: 2014-05-21 / Fundação de Amparo à Pesquisa do Estado de Goiás - FAPEG / Mycobacterium massiliense (MM) has been associated as the causative agent of many nosocomial outbreaks related to laparoscopy, arthroscopic and wound infections. Several outbreaks have been reported in Brazil. The cities of Goiânia, Rio de Janeiro and Belem reported a high number of cases in 2006 and 2007. The iron ion (Fe) is extremely important for many biochemical processes in all organisms and, in the case of microorganisms, the success of the infection. Microorganisms synthesize molecules called siderophores (SD) to aid Fe uptake. Micobactin and carboximicobactin are the SDs that has been described in mycobacteria. One of the genes responsible for the assembly of these SD in M. tuberculosis is the mbtb. A MM strain, which belongs to the outbreak that happened in Goiânia (MM GO06) had its genome sequenced and the analysis revealed that the species has a putative gene with high similarity to M. tuberculosismbtb, which could be an indication that MM also synthesizes a siderophore molecule and that this can be helping this mycobacteria to install the infection in the host. It is known that in the absence of mbtb gene M. tuberculosis do not synthesize their SD. To estimate whether a gene similar to mbtb and with the same function is present in MM (smbtb) will assist in the understanding of the infection mechanisms of MM and discover new drug targets for treating infections with this microorganism. Total RNA was obtained from cultures grown at different concentrations of Fe. Real time PCR was performed targeting the smbtb to evaluate the expression of this gene during bacterial growth in each condition. The expression of smbtb was higher with the increase of the availability of iron. In vivo studies with mice supplemented with or chelated fromiron showed expression profile of smbtb different from those obtained in in vitro studies. In mice, M. massiliense smbtb expressed at higher levels when the animal were treated for iron depletion. Thus, we have evidence that smbtb is involved in iron uptake both for subsequent storage, when this ion is available, and for prompt use in the metabolism of the bacteria when it is not in an environment where there is availability of this ion. / Mycobacterium massiliense (MM) tem sido associado como agente causador de vários surtos nosocomiais relacionados à laparoscopia, artroscopia e infecções de feridas. Inúmeros surtos têm sido reportados no Brasil. As cidades de Goiânia, Rio de Janeiro e Belém apresentaram um alto número de casos em 2006 e 2007. O íon ferro é extremamente importante para vários processos bioquímicos em todos os organismos e, no caso dos microrganismos, para o sucesso da infecção. Para auxiliar a captação de Fe durante este processo, os microrganismos sintetizam moléculas chamadas sideróforos, que desempenham esta função. Micobactina e carboximicobactina são os sideróforos que já foram descritos em micobactérias. Um dos genes responsáveis pela síntese dos sideróforos em M. tuberculosis é o mbtb. Um isolado de MM, com origem no surto que aconteceu em Goiânia (MM GO06) teve seu genoma sequenciado e sua análise revelou que esta espécie possui um gene putativo com alta similaridade com o mbtb de M. tuberculosis, o que poderia indicar que MM também sintetiza sideróforos e que está molécula poderia estar auxiliando esta micobactéria a instalar a infecção no hospedeiro. Sabemos que a ausência do gene mbtb em M. uberculosis torna esta micobactéria incapaz de sintetizar sideróforos. Avaliar se um gene similar ao mbtb e com a mesma função está presente em MM (smbtb) irá auxiliar o entendimento dos mecanismos de infecção de MM e a descoberta de novos alvos para drogas para o tratamento de infecções causadas por MM. RNA total foi obtido de culturas onde MM foi crescido em diferentes concentrações de ferro. Realizou-se Real Time PCR para o gene smbtb a fim de avaliar a expressão deste gene durante o crescimento bacteriano em cada condição. A expressão do sbmtb aumentou com o aumento da disponibilidade de ferro. Estudos in vivo com camundongos suplementados ou privados do íon ferro apresentaram um perfil de expressão diferente daquele obtido nos estudos in vitro. Em camundongos, MM expressou smbtb em altos níveis nos animais que foram tratados com quelante para o íon ferro. Evidenciamos então, que smbtb pode estar envolvido na captação de ferro tanto para armazenamento deste íon, quando o mesmo está isponível, quanto para a utilização imediata no metabolismo da bactéria, quando há uma baixa disponibilidade de ferro no ambiente que MM se encontra.
|
Page generated in 0.052 seconds