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1
Meola, Alain. "Les quinolones : étude chimique et pharmacologique, synthèse." Bordeaux 2, 1991. http://www.theses.fr/1991BOR2P090.
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Laurens, Gabrielle. "Quinolones et choc anaphylactique : à propos d'un bilan réalisé au Centre régional de pharmacovigilance du Languedoc-Roussillon." Paris 5, 1992. http://www.theses.fr/1992PA05P158.
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Ballesté, Delpierre Clara Celia. "Quinolone resistance acquisition and impact on virulence in Salmonella enterica: a cost-benefit matter." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/396155.
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Infections due to Salmonella enterica are of great concern worldwide as they represent an important cause of morbidity and mortality.
Resistance to antibiotics used to treat salmonellosis has emerged along the years, and thus, the treatment of choice has been changing in order to adapt to the new features of the circulating pathogens causing disease. Currently, fluoroquinolones, mainly represented by ciprofloxacin and ofloxacin, are widely used to treat this kind of infections although other antimicrobial classes as well as new generations of fluoroquinolones are sometimes required when treatment failure occurs. This situation is mainly due to the rise in the number of isolates showing nalidixic acid resistance associated with a decrease in the susceptibility to fluoroquinolones (e.g. ciprofloxacin). Moreover, the spread of multidrug resistant isolates carrying several resistance plasmid or chromosomally-located determinants also explains, in part, the decrease in the efficacy of the current treatment and represents an important issue.
Despite this trend, a low frequency of fluoroquinolone-resistant Salmonella enterica isolates are still reported in the literature, a fact that has been the object of attention in our research group. In order to explain the current scene, we have hypothesized a presumable link between quinolone-resistance acquisition and the decrease in the virulence features among this species.
This PhD thesis addresses the context of Salmonella from different perspectives, including an epidemiological approach as well as in vitro models in order to understand the biology of this pathogen and its relation with quinolone resistance. In order to develop our hypothesis, the following specific objectives were defined: 1) Evaluation of the clonal relatedness of S. Enteritidis and S. Typhimurium clinical isolates using two different typing techniques, 2) Analysis of the outer-membrane subproteome of S. Typhimurium SL1344, 3) Investigation of the molecular mechanisms of quinolone resistance and their regulation, 4) Assessment of virulence-related properties in clinical and in vitro-selected mutants of Salmonella enterica isolates presenting different degrees of susceptibility/resistance to quinolones, 5) Identification of novel genes potentially involved in quinolone resistance and/or virulence in S. Typhimurium, 6) Genome comparison of S. Typhimurium isolates causing invasive versus non-invasive salmonellosis from different geographical areas.
These objectives have been fulfilled in 5 papers, a manuscript and additional results.Las infecciones debidas a Salmonella enterica son de gran relevancia clínica ya que representan una importante causa de mortalidad y morbilidad en todo el mundo. Debido a la aparición de resistencia a los antibióticos utilizados para el tratamiento de la salmonelosis, la terapia de elección ha ido cambiando con el tiempo para adaptarse a las nuevas características de los patógenos circulantes causantes de la enfermedad. Actualmente, las fluoroquinolonas, representadas mayoritariamente por la ciprofloxacina y ofloxacina, son los antibióticos más usados contra estas infecciones, aunque en algunos casos es necesario recurrir a otras familias de antibióticos. Esto es debido al aumento en el número de casos resistentes al ácido nalidíxico, asociado a un descenso en la sensibilidad a las fluoroquinolonas, como la ciprofloxaciona. A pesar de esta tendencia, el número de casos reportados de Salmonella enterica altamente resistente a fluoroquinolonas permanece bajo. El estudio de esta inusual situación es una de las líneas de nuestro grupo de investigación siendo la hipótesis de partida la existencia de un vínculo entre adquisición de resistencia a quinolonas y una disminución de las características vinculadas a la virulencia en esta especie. La presente tesis doctoral aborda el contexto de la Salmonella desde diferentes perspectivas, incluyendo una aproximación epidemiológica así como modelos in vitro para entender la biología de este patógeno y su relación con la resistencia a quinolonas. Este trabajo incluye 5 artículos científicos, un manuscrito y resultados adicionales que responden a los siguientes objetivos: 1) Evaluación de la relación clonal entre aislados clínicos de S. Enteritidis y S. Typhimurium mediante el uso de dos técnicas distintas; 2) Análisis del subproteoma de la membrana externa de S. Typhimurium SL1344; 3) Investigación de los mecanismos moleculares de resistencia a quinolonas y de su regulación; 4) Evaluación de las propiedades relacionadas con la virulencia en aislados clínicos así como en mutantes seleccionados in vitro de Salmonella enterica con diferentes niveles de sensibilidad/resistencia a quinolonas; 5) Identificación de nuevos genes potencialmente implicados en la resistencia a quinolonas y/o virulencia en S. Typhimurium; 6) Comparativa de los genomas de aislados clínicos de S. Typhimurium causantes de salmonelosis invasiva versus no-invasiva procedentes de diferentes áreas geográficas.
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Parte, Aidan Charles. "4-quinolone antibacterials and temperature." Thesis, University College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267566.
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Gropper, Achitoov Savion. "Absorption, safety, and tolerability of a topical quinolone (Absorción, seguridad y tolerabilidad de una quinolona tópica)." Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/325687.
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Ozenoxacino es una quinolona no fluorada desarrollada como una crema al 1% para el tratamiento tópico del impétigo en adultos y niños (a partir de 2 meses de edad). Ozenoxacino ha demostrado una potente actividad antibacteriana contra diferentes patógenos involucrados en infecciones bacterianas agudas de la piel y estructuras cutáneas.
Los estudios de desarrollo preclínico han demostrado que ozenoxacino muestran un amplio margen de seguridad, falta de efectos adversos generalmente asociados con quinolonas fluoradas, (como fototoxicidad, fotoalergia, potencial de sensibilización y toxicidad de tendones y articulaciones) y un bajo potencial de absorción.
El desarrollo clínico ha incluido diferentes ensayos clínicos con el fin de evaluar la absorción, seguridad, tolerabilidad y eficacia de aplicaciones tópicas de ozenoxacino. En estos estudios, ozenoxacino ha sido evaluado en diferentes condiciones (diferentes formulaciones, concentraciones, regímenes de administración, duraciones de tratamiento, extensiones de la piel y condiciones de la piel) en voluntarios sanos y en pacientes adultos con lesiones traumáticas secundariamente infectadas, y en pacientes pediátricos y adultos con impétigo.
El presente trabajo doctoral incluye los siguientes estudios llevados a cabo para evaluar específicamente la absorción, la seguridad y la tolerabilidad de aplicaciones tópicas de ozenoxacino:
• In-vitro percutaneous absorption and metabolism studies.
• Systemic bioavailability, safety and tolerability studies.
• Skin tissue exposure study.
• Dermal tolerability studies.
• Systemic bioavailability and safety in impetigo.
Estos estudios han sido incluidos en diferentes publicaciones que se presentan y discuten en este trabajo de doctorado.
Este trabajo incluye además, una breve revisión de quinolonas, infecciones agudas bacterianas de la piel y estructuras cutáneas, antibióticos tópicos, fármacos en desarrollo para infecciones dermatológicas y ozenoxacino.Ozenoxacin is a non-fluorinated quinolone currently developed as a 1% cream for the topical treatment impetigo in adults and children (aged 2 months and older). Ozenoxacin has demonstrated a potent antibacterial activity against different pathogens involved in acute bacterial skin and skin structure infections. Preclinical development studies have demonstrated that ozenoxacin show a broad safety margin, a lack of adverse effects usually related to fluorinated quinolones (such as phototoxicity, photoallergenic, sensitizing potential, and tendon and articular toxicity), and a low potential of absorption. The clinical development of ozenoxacin has included different clinical trials to evaluate the absorption, safety, tolerability, and efficacy of topical applications of ozenoxacin. In these studies ozenoxacin has been evaluated under different conditions (different formulations, concentrations, administration regimens, treatment durations, skin extensions and skin conditions) in healthy volunteers and in adult patients with secondarily infected traumatic lesions, and in pediatric and adult patients with impetigo. The present PhD work includes the following clinical studies conducted specifically to evaluate the absorption, safety, and tolerability of ozenoxacin: • In-vitro percutaneous absorption and metabolism studies. • Systemic bioavailability, safety and tolerability studies. • Skin tissue exposure study. • Dermal tolerability studies. • Systemic bioavailability and safety in impetigo. These studies have been published in different papers that are presented and discussed in this PhD work. This work includes as well, a brief review of quinolones, acute bacterial skin and skin structure infections, topical antibiotics, drugs in development for dermatological infections, and ozenoxacin.
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Hodgkinson, James Thomas. "The synthesis of Pseudomonas Quinolone Signal analogues and their effects on quinolone signalling in Pseudomonas aeruginosa." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610117.
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Yvon, Jean-François. "Quinolones - fluoroquinolones : évolution de la résistance, apport des nouvelles molécules." Paris 5, 1998. http://www.theses.fr/1998PA05P047.
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Le, Bellego Carl. "Sensibilité "in vitro" de "Chlamydia trachomatis" aux antibiotiques : application aux nouvelles quinolones." Paris 5, 1993. http://www.theses.fr/1993PA05P217.
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Mitelheiser, Sylvain. "DNA gyrase, quinolone drugs and supercoiling mechanism." Thesis, University of East Anglia, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423811.
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Hallett, Paul. "Studies on DNA gyrase and quinolone drugs." Thesis, University of Leicester, 1990. http://hdl.handle.net/2381/35242.
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A study has been conducted aimed at the generation and characterisation of mutations in the Escherichia coli gyrA gene, resistant to the quinolone group of antibacterial agents. Preliminary studies on quinolone-resistant mutants of strains that over-express the DNA gyrA gene, revealed the over-production of a 60 KDa protein which was partially purified. This 60 KDa protein was found to be similar, but not identical to the E. coli heat shock protein GroEL. The gyrA gene has been recloned in the 8.0 kb plasmid pPH3, which contains the gene under the stringent control of the hybrid tac promoter. The E. coli strain JMtacA containing pPH3 exhibits no expression of the gyrA gene in the absence of the inducer (IPTG), but over-produces the protein at greater than 20% of the total soluble cell protein after induction. The optimisation and purification of the GyrA subunit from JMtacA is also described. A fragment was subjected to site-directed mutagenesis which contained the TCG codon for serine-83, which was mutated to alanine (GCG). The mutant showed a 15x increase in MIC50 compared to wild-type. The mutated GyrA subunit was over-produced, complexed with wild-type GyrB subunit and used in various assays for reactions performed by DNA gyrase. The ID50 was determined for supercoiling, decatenation, relaxation of negatively supercoiled DNA, and cleavage of supercoiled DNA. The cleavage reaction mediated by Ca++ was also investigated. The technique of gap-misrepair mutagenesis, geared to the generation of single, random point mutations on a plasmid was also used on the plasmid pPH3, to generate a quinolone-resistant mutant of the gyrA gene. The mutant isolated (GMIOO) was also over-produced and compared to wild-type in various assays. The mutation was determined by DNA sequencing to be glutamine-106 to arginine.
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Boughougal, Amina. "Synthèse et caractérisation de composés de coordination antimicrobiens." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1260.
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Le développement de composés de coordination biologiquement actifs (antimicrobiens, les anti-inflammatoires, les antifongiques, les anti-oxydants et les anticancéreux) est un domaine de la chimie inorganique en évolution rapide, susceptible d'avoir un impact direct sur l'amélioration de la qualité de la vie. Les complexes métallo-antibiotique tirent parti de l'effet synergique pour aboutir à une activité pharmacologique améliorée. La reconnaissance du rôle des ions métalliques dans les systèmes biologiques et dans le traitement de diverses maladies attire l'attention sur les avantages d'étudier l'interaction des ions métalliques avec les molécules de médicaments organiques. Dans la continuité avec les travaux précédents de l’équipe, nous nous intéressons à la synthèse de nouvelles familles de complexes métaux-antibiotiques associant l’activité antiseptique d’un ion métallique à un ou deux types de molécules bioactives. Leurs actions additives doivent avoir un effet synergique et conduire à des traitements plus efficaces et devraient fortement minimiser les risques d'apparition de bactéries mutantes. Au cours de ce travail, nous avons réussi à synthétiser le premier complexe métal-antibiotique associant deux types d'antibiotiques différents comme ligands du Zn(II). Des études comparatives montrent qu'il a une meilleure activité antibactérienne contre E. Coli, E. Aureus, E. Feacalis que les antibiotiques parents et les complexes ne contenant qu'un seul de ces antibiotiques. Cela ouvre un nouveau concept appelé « Assemblage de Biomolécules Multi-actifs, ABM ». De plus, nous décrivons la synthèse et la caractérisation de nouveaux ligands antimicrobiens trifluorométhylésDevelopment of novel coordination complexes with diverse biological activities (antimicrobial, anti-inflammatory, antifungal, antioxidant and anticancer) is a rapidly evolving field of inorganic chemistry with potential direct impact on quality of life. Metal–drug complexes are of increasing interest in bioinorganic chemistry, leveraging the synergistic effect to lead to compounds with improved pharmacological activity. The recognition of the role of metal ions in biological systems and in treatment of various diseases calls attention to the benefits of studying the interaction of metal ions with organic drug molecules. In continuation with previous works of team, we focus here on the synthesis of new families of metal-antibiotic complexes associating, on one single-molecule, the antiseptic activity of a metal ion with the bioactivity of one or two type of bioactive molecules. Their additive actions have a synergetic effect and lead to more effective and shorter treatments and should strongly minimize the risks for appearance of bacteria mutants. In this work, we succeeded to synthesis the first metal-antibiotic complex associating two types of different antibiotic as ligands with Zn(II). The structure in the solid state of this new complex was established together with the studies of the chemical-physical properties. Comparative studies show it has a better antibacterial activity against (E.Coli, E,Aureus, E.Feacalis ) than parent antibiotics and complexes with only one of the antibiotic. This open a new concept named as Multi-Active Biomolecule Assembly. Moreover, the synthesis and characterisation of new trifluorométhylated antimicrobial ligands are described
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Ilangovan, Aravindan. "Structural studies of Pseudomonas quinolone signal regulator PqsR." Thesis, University of Nottingham, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580285.
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Pseudomonas aeruginosa is an opportunistic pathogen with a wide host range. It causes serious infection in cyctic fibrosis patients and patients with suppressed immunity. Most of the virulence and adaptational characters of this pathogen are controlled by quorum sensing. Quorum sensing in P. aeruginosa has two types of system, the first quorum sensing system is facilitated by N-acyl homoserine lactones which is further constituted by two system las and rhl system. The second type of quorum sensing system is facilitated by alkyl quinolones (AQ) and thus called the AQ signalling system. The AQ quorum sensing system plays a vital role in P. aeruginosa as it holds regulatory control over the rhl system and also is associated with the virulence factors such as pyocyanin, lectin and biofilm maturation. This system includes the phnA/B genes which produce the precursor molecule anthranilate and the pqsABCDE operon, which produces the first signal molecule 2-heptyl-4-quinolone (HHQ). HHQ gets converted to 2-heptyl-3hydroxy-4-quinolone also called Pseudomonas quinolone signal (PQS) which is the second signal molecule. The conversion of HHQ to PQS is facilitated by PqsH, an oxygen dependent monooxygenase which is not part of the pqsABCDE operon. PqsR, a transcriptional regulator of the LysR family of transcriptional regulator, holds transcriptional control over the phnA/B genes and pqsABCDDE operon. Avirulent phenotypes were observed with P. aeruginosa strains lacking PqsR, suggesting its important role in virulence. The cloning, expression, purification and crystal structure solution of PqsR coinducer binding domain has been described in this thesis. The structure of PqsR CBO shows a typical LTIR fold with 6 helices and 8 ~-strands. The structure also shows a unique dimer interface, unique hydrophobic pocket. In the apo-structure, two MPO molecules stabilised the hydrophobic pocket. The PqsR CBO - NHQ complex structure shows the ligand bound to the hydrophobic pocket with the quinolone head group buried deep within the protein and the alkyl chain bent and extending parallel to the dimer interface. PqsR is a potential anti-quorum sensing
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Willmott, Christopher John Rowan. "The interaction of quinolone antibacterials with DNA gyrase." Thesis, University of Leicester, 1993. http://hdl.handle.net/2381/35181.
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Quinolone drags are a clinically significant family of antibacterial compounds that are known to affect the activity of DNA gyrase, an essential bacterial enzyme involved in controlling the topological state of DNA, Gyrase holoenzyme, a complex of two A and two B subunits, can introduce negative supercoils into DNA using energy derived from the hydrolysis of ATP. Although addition of quinolones rapidly inhibits the supercoiling activity of gyrase, it was found that quinolone-dependent DNA cleavage was a slow process, leading to the suggestion that there may be two levels of interaction between quinolones and the gyrase-DNA complex. Rapid gel-filtration experiments have shown that stable quinolone binding requires the presence of both gyrase and DNA; no significant binding was found to either gyrase or DNA alone. Enzyme containing gyrase A protein with the mutation Ser83 to Trp (which is known to confer quinolone resistance) showed greatly reduced drug binding. It is concluded that efficiency of binding is primarily determined by the gyrase A subunits. Investigation of transcription by T7 and Escherichia coli RNA polymerases has found that quinolone-mediated stabilisation of a gyrase-DNA complex prevents passage of polymerase along the template. Inhibition of transcription required the presence of gyrase and quinolone together; RNA polymerase was unaffected by either quinolone or gyrase alone, implying that polymerase can normally pass or displace gyrase. In the presence of ciprofloxacin, gyrase was found to shield a region of about 26 bp of DNA from transcription by T7 RNA polymerase, with especially strong protection of a 20 bp core. Preliminary experiments performed using an in vitro DNA replication system suggest that DNA polymerases may be similarly interrupted by a gyrase-quinolone-DNA complex.
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MacDonald, Alasdair Arthur. "Synthesis of quinolone antibiotics by Diversomer™ technology." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/11075.
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The generation of chemical diversity by the parallel synthesis of potential drug candidates has been demonstrated by Parke-Davis' DIVERSOMER Technology. This technology combines solid phase organic synthesis, (SPOS), miniaturization, automation, integration and custom equipment to generate "libraries" of discrete compounds. The research programme involved a detailed analysis of the synthesis of the quinolones, a well-known class of antibacterial agents of which over 6000 compounds are known to date. A solution phase synthesis was developed which was compatible with solid phase reaction conditions and also amenable to parallel SPOS protocols. Results of these studies and the parallel synthesis, isolation, purification and analysis of a quinolone library will be discussed. Additionally, an alternative "solid support" for the SPOS of quinolones will be discussed. Construction of the quinolones with a tetrabenzo[a,c.g.i]fluorene, (Tbf) handle enables controlled adsorption onto and off porous graphitised carbon (PGC). The Tbf/PGC system also has demonstrated utility for automated, parallel purification strategies.
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Hayes, Michelle. "β-lactam and quinolone resistance in Aeromonas spp." Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/20558.
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The majority of Aeromonas spp. are innately resistant to ampicillin, therefore the aim of this thesis was to examine the resistance mechanism of A.salmonicida subspp. achromogenes and A.hydrophila to β-lactam antibiotics. Previous researchers had revealed the presence of two β-lactamases in the motile Aeromonas spp., a penicillinase with carbapenemase activity and a cephalosporinase. However, it was demonstrated in this thesis, that these β-lactamases had not been purified completely and that three β-lactamases could be purified from A.salmonicida subspp. achromogenes and A.hydrophila. Anion and cation exchange chromatography were employed to separate the β-lactamases of the strains which had been induced with sub-MIC doses of ampicillin, cefoxitin or imipenem. Substrate profiles of these purified β-lactamases revealed the presence of a cephalosporinase, a penicillinase and a highly unusual carbapenemase which cannot be detected with nitrocephin. Inhibitor profiles showed that the cephalosporinase and the penicillinase were serine-based, whereas the carbapenemase was a metallo-enzyme but was unusually sensitive to zinc and may be a new class of metallo-β-lactamase. The cephalosporinase is probably a class C β-lactamase whereas the penicillinase is probably a class A β-lactamase. An ampicillin-sensitive species, A.salmonicida subspp. salmonicida was also examined and found to contain a carbapenemase and a cephalosporinase, but no penicillinase, which will explain its sensitivity to ampicillin. The expression of these two β-lactamases appears to be co-regulated as the cephalosporinase was only expressed in the uninduced strain and the carbapenemase activity was much higher post-induction. During this PhD., the first quinolone-resistant clinical isolate of A.hydrophila was found. The gene encoding the α subunit of the DNA gyrase was therefore amplified and sequenced and compared with the sequence of a sensitive strain. A mutation was found in the codon of amino acid 83 which affected the ability of the quinolone drugs to bind to the DNA gyrase. Five laboratory mutants of A.hydrophila were also selected with either nalidixic acid or ciprofloxacin and the changes in the sequences of the gyrA genes were also determined to occur at amino acid 83 and/or 87.
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Lenz, Jörn-Benjamin [Verfasser], and Peter [Akademischer Betreuer] Heisig. "The ternary gyrase-DNA-quinolone complex : from molecular modelling to understanding quinolone action and resistance / Jörn-Benjamin Lenz. Betreuer: Peter Heisig." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/102038350X/34.
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Allali, Nourredine. "Analyse du rôle des gènes chromosomiques tldD et tldE dans le système poison/antidote ccd et dans la maturation de la microcine B17." Doctoral thesis, Universite Libre de Bruxelles, 2002. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211343.
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Peyramaure, Elisabeth. "Distribution de trois classes d'antibiotiques dans l'organisme : les macrolides, les quinolones et les céphalosporines." Paris 5, 1991. http://www.theses.fr/1991PA05P193.
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Robaux, Hubert. "Contribution à l'étude du mécanisme d'action des quinolones : implication de métaux (magnésium et cuivre) dans la formation de chélates avec une base purique ou la tyrosine et dans l'interaction avec les topoisomérases." Nancy 1, 1990. http://www.theses.fr/1990NAN10554.
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Sousa, Rafaela Rogério Floriano de. "Pesquisa de genes de resistência a quinolonas em bacilos Gram negativos de origem clínica e ambiental." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/6/6135/tde-27032014-091736/.
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Introdução. Quinolonas são antimicrobianos sintéticos que inibem as enzimas DNA-girase e topoisomerase IV resultando na morte bacteriana. São altamente eficazes no tratamento de infecções bacterianas, especialmente causadas por bactérias Gram negativas, e portanto amplamente utilizados na medicina humana e veterinária, na qual também são empregados como profiláticos. Porém, o uso indiscriminado e inadequado levou ao aumento de bactérias resistentes a estes compostos. Esta resistência pode ocorrer devido a mutações nas enzimas DNA-girase e topoisomerase IV, e também por genes contidos em plasmídeos. Estes últimos são os principais responsáveis pela disseminação e circulação da resistência entre o meio ambiente e o ambiente hospitalar. Objetivos. Pesquisar genes de resistência a antimicrobianos do grupo das quinolonas em bactérias Gram negativas de origem clínica e ambiental que apresentam resistência fenotípica a este grupo. Material e Métodos. 73 cepas de Enterobacteriaceae e Aeromonas sp. de origem clínica e ambiental foram selecionadas para o estudo, e avaliadas quanto à sensibilidade aos antimicrobianos do grupo das quinolonas e à pesquisa de genes de resistência a este mesmo grupo e mutações no gene que codifica a enzima DNA-girase por meio de PCR e sequenciamento. Resultados. Das 73 cepas previamente selecionadas para compor o estudo, 65 foram utilizadas, devido à exclusão de perfis clonais similares. Nestas, foram observados os genes, qnrS1 (1,5 por cento ), qnrS2 (26,2 por cento ), qnrB1 (3,1 por cento ), qnrB19 (12,3 por cento ), qnrD1 (1,5 por cento ), aac(6)-Ib-cr (10,8 por cento ), oqxA (43,1 por cento ) e oqxB (41,5 por cento ), e duas variantes determinadas qnrB-like (3,1 por cento ) e qnrB69-like (1,5 por cento ). Os genes qnrA, qnrC e qepA não foram identificados. Mutações na enzima DNA-girase foram observadas em 97,9 por cento das cepas positivas para algum dos genes pesquisados. Em 4 cepas foi possível estabelecer a associação do gene aac(6)-Ib-cr com integron de classe 1. Foi realizado sequenciamento e caracterização do plasmídeo completo onde estava inserido o gene qnrD1. Conclusões. Este estudo relata pela primeira vez no Brasil a ocorrência dos genes qnrS2, oqxA e oqxB, a associação entre o elemento genético integron de classe 1 e o gene aac(6)-Ib-cr, e o gene qnrD1 e a caracterização do plasmídeo completo onde este estava inserido. Os genes qnrB1, qnrB19, e aac(6)-Ib-cr, anteriormente apenas relatados em cepas clínicas, foram observados em cepas ambientais. Os resultados deste estudo mostram alta frequência de genes de resistência a quinolonas tanto em isolados clínicos quanto em isolados ambientais, alertando quanto à disseminação da resistência entre fontes diferentes, e possível manutenção destes genes por cepas ambientais.Introduction. Quinolones are synthetic antimicrobial agents that inhibit DNA gyrase and topoisomerase IV enzymes resulting in bacterial death. They are highly effective in the treatment of bacterial infections, especially the ones caused by Gram negative bacteria, as well as for prophylaxy. Therefore they are widely used in human and veterinary medicine. However, indiscriminate and improper use led to an increase of bacteria resistance to these compounds. This resistance can be due to mutations in DNA gyrase and topoisomerase IV enzymes and also by genes contained in plasmids, which are mainly responsible for the spread and transmission of resistance between the environment and the hospital set. Objectives. To search for genes of resistance to quinolone antimicrobial agents in Gram-negative bacteria from clinical and environmental strains that present phenotypic resistance to this group. Material and Methods. 73 strains of Enterobacteriaceae and Aeromonas spp., from clinical and environmental origin, were selected for this study, and evaluated for antimicrobial susceptibility of quinolone and search of resistance genes in this same group and also for mutations in the gene encoding the enzyme DNA gyrase by PCR and sequencing. Results. Of the 73 strains previously selected to compose this study, 65 were used, due to the exclusion of similar clonal profiles. In these, genes qnrS1 (1.5 per cent ), qnrS2 (26.2 per cent ) qnrB1 (3.1 per cent ), qnrB19 (12.3 per cent ) qnrD1 (1.5 per cent ) aac(6\')-Ib-cr (10.8 per cent ) oqxA (43.1 per cent ) and oqxB (41.5 per cent ) were observed, and two variants were named as qnrB-like (3.1 per cent ) and qnrB69-like (1.5 per cent ). The qnrA, qnrC and qepA genes were not identified. Mutations in DNA gyrase enzyme were observed in 97.9 per cent of the positive strains for at least one of the genes studied. It was possible to establish the association of aac(6\')-Ib-cr with class 1 integron gene in four strains. Complete sequencing and characterization of plasmid qnrD1, where the gene was inserted, was performed. Conclusions. This study reports, for the first time in Brazil, the occurrence of qnrS2, oqxA and oqxB genes, the association between genetic element integron class 1 gene and the aac (6 \')-Ib-cr, and qnrD1 gene and the characterization of the complete plasmid where this was inserted. qnrB1, qnrB19, and aac(6\')-Ib-cr genes, previously only reported in clinical strains, were observed in environmental strains. The results of this study show a high frequency of quinolone-resistance genes for both clinical and environmental isolates, warning about the spread of resistance through different sources, and the possible maintenance of these genes by environmental strains.
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Minarini, Luciene Andrade da Rocha. "Estudo dos mecanismos de resistências às quinolonas em enterobactérias isoladas de alguns estados brasileiros." Universidade de São Paulo, 2008. http://www.teses.usp.br/teses/disponiveis/60/60135/tde-01042009-103754/.
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Este estudo foi elaborado com o objetivo de elucidar os mecanismos de resistência às quinolonas presentes em enterobactérias isoladas de pacientes de duas regiões metropolitanas brasileiras. Foram avaliadas possíveis alterações nas proteínas relacionadas com o sítio de ação das quinolonas, bem como a presença de plasmídeos e integrons que carregam determinantes gênicos que codificam resistência às quinolonas. A associação destes com mecanismos plasmideais de resistência aos antibióticos -lactâmicos também foi analisada. Foram avaliadas 257 enterobactérias resistentes ao ácido nalidíxico isoladas de pacientes hospitalizados e da comunidade no período de 2000 a 2005. Por PCR e seqüenciamento, foram analisadas as mutações presentes nos genes cromossômicos gyrA e parC e as estruturas gênicas associadas com determinantes plasmideais de resistência às quinolonas, Qnr, e aos -lactâmicos de amplo espectro. Foram determinados os perfis plasmideais e a transferabilidade dos plasmídeos que carrearam estes determinantes. A extração e a análise das proteínas de membrana externa foi realizada para avaliar uma possível perda ou diminuição da expressão de porinas, também relacionada com os mecanismos de resistência avaliados. Todas as amostras foram resistentes ao ácido nalidíxico, apresentando concentração inibitória mínima (CIM) superior a 16 g/mL, e em média, 70% apresentaram diminuição de sensibilidade às fluoroquinolonas testadas. De 257 enterobactérias resistentes ao ácido nalidíxico, em seis enterobactérias (2,3%), incluindo 3 E. coli, 2 K. pneumoniae e 1 C. freundii foi encontrado o gene qnrB. Cinco linhagens apresentaram suas seqüências idênticas ao gene qnrB2, e uma linhagem, C. freundii JF79, apresentou uma seqüência idêntica ao gene qnrB8. Em uma linhagem de E. cloacae foi detectado o gene qnrA1 (0,37%). Os genes qnrA e qnrB apresentaram-se localizados em plasmídeos que apresentaram de 55 a 180 kilobases. A análise da estrutura gênica indicou que os genes qnrA1 e qnrB2 estavam associados com um integron classe 1 e localizados entre o elemento ISCR1 e a segunda cópia do segmento conservado 3. Na coleção bacteriana avaliada, as principais mutações observadas foram nos códons 83 e 87 em gyrA, e nos códons 80 e 84 em parC. Todas as enterobactérias que exibiram unicamente mutações no gene gyrA apresentaram CIM 16 µg/mL para o ácido nalidíxico. A diferença encontrada nos valores da CIM de fluoroquinolonas em enterobactérias que apresentaram as mesmas substituições em GyrA e ParC foi explicada pela ausência ou diminuição da expressão de porinas. Em relação à produção de -lactamase de espectro ampliado (ESBL), sua presença foi comprovada em 24 (9,3%) enterobactérias. O seqüenciamento de blaCTX-M identificou 18 determinantes: CTX-M-2 (n=13), incluindo dois novos variantes, CTX-M-8 (n=2) e CTX-M-9 (n=3) mediados por plasmídeos de 48 a 180 kilobases, não conjugativos, em maioria. O gene blaSHV-5 foi detectado em seis enterobactérias. Todos os determinantes do grupo 2 apresentaram-se associados com um elemento ISCR1, enquanto que aqueles do grupo 9 estiveram relacionados com ISEcp1. Concluindo, o principal mecanismo de resistência às quinolonas detectado foi a presença de substituições em GyrA e ParC, apesar de outros mecanismos, como a diminuição da expressão de porinas estarem envolvidos nas enterobactérias avaliadas. A associação da produção de ESBL foi significativa devido ao encontro de uma grande diversidade de genótipos circulando na comunidade, com uma predominância de enterobactérias produtoras de CTX-M. Quanto aos determinantes Qnr descritos neste estudo, que notoriamente foram os primeiros relatos no Brasil, somente dois deles apresentaram-se relacionados com a produção de ESBL.The aim of this study was to investigate the main mechanisms of quinolone resistance among enterobacterial isolates recovered from hospitalized patients and outpatients in Brazil. The modification of the quinolone targets with changes of DNA gyrase and of topoisomerase IV genes and the presence of determinants codifying plasmid- mediated quinolone and oxymino- cephalosporins resistance were investigated. Two hundred fifty seven non-duplicate nalidixic-acid resistant enterobacterial isolates recovered from January 2000 to May 2005 were analysed. Mutations in the topoisomerases gyrA and parC genes and the genetic structures surrounding Qnr and CTX-M determinants were recognized by PCR and sequencing. Conjugation experiments were performed to determine whether the qnr- and blaCTX-M carrying plasmids were self transferable. Also, decrease in the level of porin expression related to quinolone resistance was assessed. All enterobacterial isolates were resistant to nalidixic-acid, showing minimal inhibitory concentrations (MIC) 16 g/mL and 70% of these isolates showed decreased susceptibility to fluoroquinolone. Six qnrB-positive (2.3%) out of 257 nalidixic-acid resistant enterobacterial isolates, were identified, including 3 Escherichia coli, 2 Klebsiella pneumoniae and 1 Citrobacter freundii. Five isolates had an identical qnrB2 sequence and one isolate, C. freundii 79, possessed the qnrB8. A single Enterobacter cloacae carrying a plasmid encoding qnrA gene was identified (0.37%). All isolates were negative for the qnrS genes. Plasmid-mediated quinolone resistance ranged from 55- to 180-kb in size. Sequence analysis of the genetic structures surrounding of the qnrA and qnrB genes identified an ISCR1 element at the left-hand boundary and a partial copy of the 3-end segment of class 1 integrons. Concerning the changes of DNA gyrase and topoisomerase IV, the most common modification in the enterobacterial isolates analyzed were present at codons 83 and 87 in GyrA and in ParC at codons 80 and 84. All isolates that exhibited mutations in gyrA gene showed nalidixic-acid MIC 16 µg/mL. The finding of different MIC values to fluoroquinolones in enterobacterial isolates with the same GyrA and ParC modification was explained by a decreasing in the level of porin expression. Regarding -lactam resistance mechanisms, twenty four (9.3%) ESBL-producing enterobacterial isolates were detected. Sequencing of the CTX-M-encoding genes identified 18 determinants belonging to CTX-M-2 (n=13), CTX-M-8 (n=2) and CTX-M-9 (n=3) groups. CTX-M-2 group determinants included blaCTX-M-2 and the two novel variants. Plasmids harboring blaCTX-M genes ranged from 48- to 180- kb in size and were not transferable, in their majority. The blaSHV-5 genes were detected in all the 6 blaCTX-M negative isolates. All alleles belonging to the group 2 were associated with ISCR1 element, while all blaCTX-M-9 genes were related to ISEcp1 element. In conclusion, alterations in the targets of quinolones, GyrA and ParC was the main mechanism of quinolone resistance identified in this study, although a decreasing of the porins expression had been identified among nalidixic-acid resistant enterobacterial isolates. In the surveyed area, the prevalence of ESBL producers was important (9.3%), provided that this finding was related to a large diversity of genotypes circulating in the community, mainly CTX-M-producing isolates. This study constituted the first epidemiological survey of QnrA and QnrB determinants among Brazilian isolates. Interestingly, the qnrB2 gene was identified in non ESBL producers isolates and qnrS genes were not found.
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Eftekharzadeh, Shirin 1967. "The attachment of quinolone based antibiotics to metallic biomaterials." Thesis, The University of Arizona, 1993. http://hdl.handle.net/10150/278347.
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A simple and effective technique for the deposition of ciprofloxacin HCl salt onto pore coated Ti-6Al-4V alloy rods has been investigated for the prevention of infection in orthopedic applications. This technique involves the electrophoretic deposition of negatively charged ciprofloxacin particles as well as the precipitation of ciprofloxacin anions on positively biased rods. Experimental variables such as applied voltage, coating time, and pH of the antibiotic solution have been investigated in terms of the amount of deposited antibiotic, the morphology of antibiotic coating, the rate of release of deposited ciprofloxacin and the antibacterial activity of the coated samples against Staph aureus and Staph epidermidis.
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Brown, Janice C. "Molecular interactions between DNA gyrase and the quinolone antibacterials." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/21651.
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DNA gyrase is an essential bacterial topoisomerase with a central role in many cellular processes. Its lack of homology to eukaryotic topoisomerases has been the basis of its role as an important drug target. The quinolone antibacterials have previously been shown to "poison" DNA gyrase of Escherichia coli, resulting in rapid bacterial cell death by a pathway which has been a subject of controversy. Following on from the finding that the complex of quinolone and gyrase on DNA results in truncated mRNAs in vitro, the results presented in this thesis show that in vivo, the addition of quinolone drugs results in the production of truncated mRNAs which are presumably translated into truncated proteins. This is expected to cause total deregulation of cellular processes and result in cell death. It has also been shown that the newer more potent quinolone drugs such as ciprofloxacin and ofloxacin have an additional effect on the bacterial cells in that the chromosome is broken down into fragments of DNA, some of which are estimated to be as small as 4kb in length. This process appears similar to the degradation of chromosomal DNA that occurs during apoptosis of some eukaryotic cells. The acquisition of quinolone-resistance in E. coli and Salmonella has also been investigated. Firstly, part of gyrA of S. typghimurium NCTC5710 was sequenced and found to be 94% homologous at the nucleotide level to the corresponding sequence of E.coli. Following on from this, clinical isolates were screened by DNA sequencing and amino acid mutations in the "quinolone resistance determining region" (QRDR) of gyrA identified. Mutations in gyrA such as serine-83 to leucine, serine-83 to phenylalanine, aspartate-87 to tyrosine, aspartate-87 to asparagine and aspartate-87 to glycine were found to have arisen in the QRDR of gyrA in common with other quinolone resistance mutations previously found. Cloning of gyrA into a vector in which the copy number could be altered confirmed that high level expression of gyrA is detrimental to the cell.
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Gunn, Mary Esther. "A modular catalytic approach towards pyridine and quinolone synthesis." Thesis, University of Leeds, 2013. http://etheses.whiterose.ac.uk/4959/.
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N-Containing heterocycles such as substituted pyridines and 2-quinolones are commonly found in drugs and agrochemicals; however, classical methods towards their synthesis often lead to limited substitution patterns. We recently described the first examples of the organocatalytic intramolecular aza-Wittig reaction in the synthesis of azoles and azines from isocyanates. The work described herein is divided into three chapters detailing attempts to expand the scope of the use of isocyanates in heterocycle synthesis. The first chapter describes the development of multicomponent synthesis of substituted pyridines incorporating the intermolecular catalytic aza-Wittig and Diels–Alder reactions; in total 31 exemplar pyridines were prepared in up to 52% yield. The reaction works well for electron-poor and heteroaromatic aldehydes, electron-rich and electron-poor cinnamic acids and push-pull enamines to give a range of substitution patterns. The use of commercially available starting materials and catalytic phosphine oxide means the process offers distinct advantages over classical methods. The development of a tandem catalytic aza Wittig/electrocyclisation process towards benzothienopyridines was also investigated. To this end benzothienoimines and azatrienes were prepared, however, the electrocyclic ring closure of the azatrienes was non-trivial with low yields of the desired pyridines even under harsh conditions. The final chapter outlines the preparation of substituted 2-quinolones from readily available urea starting materials by two methods. The first is a two-pot three-step process incorporating urea-directed oxidative Heck reaction, isocyanate formation and electrocyclisation; in total 9 exemplar 2-quinolones were prepared in up to 61% overall yield. The second is a two-pot threestep process incorporating Heck reaction, isocyanate formation and electrocyclisation; 10 exemplar 2-quinolones were prepared in up to 59% overall yield. The use of the urea directinggroup in the subsequent isocyanate formation negates the necessity for acyl azides and means no further manipulation is required to remove the directing group after 2-quinolone synthesis
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Murphy, Steven Michael. "Novel aspects of the Wittig reaction." Thesis, Northumbria University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245286.
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TAUPIN, SCHWETTERLE MARTINE. "Etude de pharmacovigilance de quatre fluoroquinolones : pefloxacine, norfloxacine, ofloxacine, ciprofloxacine." Reims, 1990. http://www.theses.fr/1990REIMM067.
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VAUGIN-BOULANGER, VERONIQUE. "Effets indesirables des nouvelles quinolones." Clermont-Ferrand 1, 1989. http://www.theses.fr/1989CLF13005.
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Padovanni, Madeleine Toran. "Pneumopathies alvéolo-interstitielles infectieuses et fluoroquinolones à propos de 46 observations." Montpellier 1, 1990. http://www.theses.fr/1990MON11021.
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Coulibaly, Songuigama. "Synthèse et activité antituberculeuse de quelques dérivés de la 1,10-phénanthrolinone." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMC407/document.
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La tuberculose est une infection humaine cosmopolite à transmission pulmonaire causée par Mycobactérium tuberculosis. Elle représente l'une des principales causes de mortalité dans le monde. La prise en charge thérapeutique de cette maladie est confrontée aujourd’hui à une forte pharmacorésistance des bacilles à la plupart des médicaments antituberculeux habituellement indiqués. Face à cette situation la recherche de nouvelles molécules plus efficaces échappant au phénomène de pharmacorésistance est encouragée par l'OMS. C'est dans ce contexte que nous avons conçu des dérivés de la 1,10-phénanthrolinone, analogues structuraux des quinolones connues pour leurs activités antituberculeuses. Ces dérivés ont été préparés par condensation de la 8-aminoquinoléine et de l'étoxyméthylènemalonate d'éthyle, suivit d'une cyclisation intramoléculaire pour conduire à la 1,10-phénanthrolinone-3-carboxylate d'éthyle. La modulation chimique de cette dernière a permis d'obtenir la plupart des dérivés de la 1,10-phénanthrolinone préparés. Les dérivés de la 1,10-phénanthrloninone synthétisés ont fait l'objet d'une évaluation de leurs activités antibacillaires. Parmi ceux-ci, certains dérivés 6-nitro-1,10-phénanthrolinones se sont particulièrement illustrés par leurs performances antibacillaires avec des CMI comprises entre 0,31 et 9,84 μM. Par ailleurs, cette activité est conservée sur les souches de mycobactéries sensibles et les souches résistantes aux quinolones ce qui fait penser à un probable mécanisme d'action différent. De plus, ces molécules se sont avérées non toxiques sur les cellules Vero avec des IC50> 100 μg/mL ( soit 16 à 64 fois leurs CMI). Notre approche pharmacochimique a conduit à l’élaboration de nouvelles molécules possédant une structure de type 1,10-phénantrolinone dont le profil chimique diffère de celui de toutes les classes chimiques d’antituberculeux existantes. Les résultats obtenus ouvrent de nouvelles voies d'investigations pour la recherche de nouveaux antituberculeux voire anti-infectieux en série chimique des 1,10-phénantrolinonesTuberculosis is a cosmopolitan human lung infection caused by Mycobacterium tuberculosis. She represents one of the main reasons of mortality in the world. therapeutic management of this disease is confronted today with a strong pharmacoresistance of bacilli to most antituberculosis habitually used. Facing this situation the research of new more efficient molecules avoiding the phenomenon of pharmacoresistance is encouraged by the WHO. It is in this context that we conceived derivatives of the 1,10-phénanthrolinone, the structural analogues of quinolones known for their antituberculosis activity. These derivatives were prepared by condensation of 8-aminoquinoline and ethyl ethoxymethylenemalonate, followed by intramolecular cyclization to give the ethyl 1,10-phenanthrolinone-3-carboxylate. The chemical modulation of the latter have allowed to get most of the 1,10-phenanthrolinone derivatives. The 1,10-phenanthrloninone derivatives synthesized were evaluated for their antibacillary activities. Among these, some 6-nitro 1,10-phenanthrolinone derivatives are particularly illustrated by their antibacillary performance with MIC included between 0.31 and 9.84 μM. In addition, this activity is kept on susceptible strains of mycobacteria and the quinolone-resistant strains , suggesting a different mechanism of action. In addition, this activity is conserved on susceptible strains of mycobacteria and quinolone-resistant strains, suggesting a different mechanism of action. Moreover, these molecules proved to be not toxic on cells Vero with IC50> 100 μg / mL (16 to 64 times their MIC). Our pharmacochimique approach has led to the development of new molecules having a structure of type 1,10-phénantrolinone from which chemical profile differs from that of all chemical classes of antitubercular drugs existent. Got results open new ways of investigations for research of new anti-tuberculosis or anti-infectious drugs in the 1,10-phenantrolinone chemical series
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Jackson, Andrew Edward. "A novel approach to #beta#-lactam and quinolone antibacterial agents." Thesis, University of Sunderland, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242127.
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The f)-lactam or azetidinone 4-membered heterocyclic nng system has been synthesised by many different synthetic strategies and these are well documented in the literature. Many of these strategies give substituted azetidinone rings displaying defined stereochemistry which are used as the building block for many modern day antibiotics. It was therefore intended to pursue a method of azetidinone ring formation using cheap and readily available starting materials employing a [2+2] cycloaddition reaction which, according to the literature, had only a few examples and was seen to be an area ripe for research. Taking urethane in anhydrous THF and metalating with n-butyl lithium, followed by the subsequent addition of phenyl vinyl sulfone, it was envisaged that the two would react in such a way to give the -l-membered azetidinone ring. It was found however that the carbon-nitrogen bond was formed but subsequent cyclisation did not follow and therefore no azetidinone was formed. Although azetidinone ring was not detected the novel compound N,N-bis-(phenylsulfonylethyl) urethane was isolated. This compound was of interest since it was hoped that it could provide a new route to substituted pyridines. Various methods were undertaken in an attempt to cyclise this molecule via the generation of a-sulfonyl carbanions and reactions with a variety of electrophiles. During our experiments no cyclised products were detected. TIle replacement of phenyl sulfonyl group with triphenylphosphonium bromide provided a new hope for azetidinone synthesis since its ability to stabilise a-sulfonyl carbanions and promote reaction with electrophiles was well established. Experiments of this nature failed to produce an azetidinone. TIle next stage of research was to investigate a new route to the production of quinolone antibiotics. Quinolones, particularly those which are furnished with a fluorine at C-6 position, are the new generation of antibiotics which exhibit a high activity and selectivity towards pathogens which have become resistant to older antibiotics such as penicillin. Needless to say their importance in the pharmaceutical industry has increased dramatically over recent years and research into the improvement of synthetic strategies towards the total synthesis of these molecules has attracted much commercial interest. Meth-Cohn showed that quinolones can be formed in excellent yield by the reaction of N-alkylformanilides in phosphorus oxychloride and activated acid chlorides e.g. methyl malonyl chloride. This approach is examined regarding the synthesis of both novel and known quinolone antibiotics (norfloxacin and ciprofloxacin). Work on this topic has produced encouraging results with the synthesis of important antibacterial intermediates.
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Critchlow, Susan Elizabeth. "The molecular basis of quinolone drug action on DNA gyrase." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/35198.
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Quinolones are a clinically-useful class of antibacterial agents known to target DNA gyrase, a bacterial type II topoisomerase. Gyrase is unique among topoisomerases in its ability to introduce negative supercoils into DNA using the energy derived from ATP hydrolysis. The active enzyme is composed of two GyrA and two GyrB subunits, forming an A2B2 tetramer of molecular weight 374 kDa. The mechanism of supercoiling by gyrase involves the ATP-driven passage of one segment of DNA through a gyrase-stabilised double-stranded break in another. Tyrosine 122 of E. coli GyrA becomes covalently attached to DNA when gyrase breaks the phosphodiester bonds of DNA during supercoiling. When this residue is mutated to serine or phenylalanine, gyrase can no longer cleave or supercoil DNA, but can bind DNA normally. Rapid-gel filtration experiments have shown that quinolones can still bind to proteins bearing these mutations, suggesting that DNA cleavage by gyrase is not required for quinolone binding. Transcription by T7 and E. coli RNA polymerases is blocked by the presence of a gyrase-quinolone-DNA complex. Mapping of the transcription termination sites in the presence of gyrase and quinolones shows that blocking occurs about 10 to 20 base-pairs upstream of the gyrase cleavage site. Blocking of transcription by T7 RNA polymerase by a gyrase-quinolone complex on DNA does not occur when the active-site tyrosine of gyrase is mutated to serine, which indicates that the polymerase blocking requires DNA cleavage. Analysis of transcription in the absence of drug suggest that RNA polymerase does not displace gyrase from the template. DNA gyrase is also the target of the CcdB protein which is encoded by the F plasmid. When its action is not prevented by CcdA protein, CcdB is a potent cytotoxin. Using in vitro transcription by T7 RNA polymerase, it has been shown that CcdB complexed with gyrase can block transcription in a similar manner to the gyrase-quinolone complex. Furthermore, in the presence of CcdA, CcdB can no longer induce gyrase to block transcription.
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Thorburn, Christine Elaine. "The effect of pharmacokinetics on the development of bacterial resistance to antibiotics." Thesis, University of East London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359992.
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Vales, Magali. "Systèmes photochromiques en série quinolone : conception, synthèse, étude des propriétés photochromiques." Aix-Marseille 2, 2002. http://www.theses.fr/2002AIX22058.
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Fochesatto, Cíntia. "Caracterização química e avaliação in vitro da atividade antimicrobiana de complexos de 99m Tc-ciprofloxacino e 99m Tc-pefloxacino." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/13156.
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A diferenciação entre processos infecciosos e inflamatórios representa um grande desafio na área de diagnóstico. A complexação do antimicrobiano ciprofloxacino (CIP) com o tecnécio (99mTc-CIP) vem sendo estudada com objetivo de desenvolver um radiofármaco com alta especificidade no diagnóstico de infecções, baseado em seu amplo espectro de atividade antibacteriana. O mecanismo de ação do fármaco consiste na ligação deste com a enzima ADN-girase da bactéria, permitindo sua ligação à bactéria ativa e a obtenção de imagens devido a fótons emitidos pelo 99mTc. Tendo em vista que o local de formação do complexo envolve os mesmos grupos funcionais responsáveis pela ligação do fármaco à enzima, sua eficácia pode ser prejudicada. A diferenciação entre processos infecciosos e inflamatórios representa um grande desafio na área de diagnóstico. A complexação do antimicrobiano ciprofloxacino (CIP) com o tecnécio (99mTc-CIP) vem sendo estudada com objetivo de desenvolver um radiofármaco com alta especificidade no diagnóstico de infecções, baseado em seu amplo espectro de atividade antibacteriana. O mecanismo de ação do fármaco consiste na ligação deste com a enzima ADN-girase da bactéria, permitindo sua ligação à bactéria ativa e a obtenção de imagens devido a fótons emitidos pelo 99mTc. Tendo em vista que o local de formação do complexo envolve os mesmos grupos funcionais responsáveis pela ligação do fármaco à enzima, sua eficácia pode ser prejudicada. O objetivo deste trabalho foi avaliar as condições ideais para ligação do 99mTc a duas quinolonas (CIP e pefloxacino), utilizando diferentes agentes redutores (SnCl2 e FSA), pH da solução e temperatura de incubação. A complexação dos fármacos ao radioisótopo 99mTc foi avaliada através do controle radioquímico, utilizando cromatografia em camada delgada. Posteriormente, testou-se sua atividade antimicrobiana in vitro utilizando diferentes microorganismos. O agente redutor FSA não foi eficiente na formação do complexo, resultando em uma concentração alta de Tc livre (37%). A formulação com Sn aumentou a formação de colóide com aquecimento (100 ºC). A complexação dos antimicrobianos ao Tc impediu sua ligação à ADN-girase. A taxa de ligação variou de 10% (filtração) a 16% (centrigugação). Além disso, verificou-se boa correlação entre a formação de colóide e quantidade de radiação ligada à bactéria em ambos os testes. Esta perda de atividade vem de encontro a alguns estudos clínicos relatados na literatura, que revelam a não diferenciação entre processos infecciosos e processos inflamatórios pelas quinolonas marcadas com 99mTc.Differentiation between inflammation and infection represents a major challenge in clinical diagnostics. Several studies using ciprofloxacin (CIP), a broad spectrum antimicrobial agent, complexed with technetium (99mTc) have been reported in order to evaluate its capacity to diagnose infections. CIP mechanism of action involves its binding with bacterial DNA-gyrase during the growth phase and the acquisition of images due to 99mTc radioactivity. The fact that the sites of complexation are the same as those involved in bacterial binding it may affect its antimicrobial activity. The objective of the present work was to evaluate the ideal conditions for the complexation of CIP and pefloxacin with 99mTc using stannous chloride and formamidinesulfinic acid (FSA) as reducing agents, different pH and temperatures. The efficiency of complexation was monitored using radiochemical control as well as thin layer chromatography. Furthermore the antimicrobial activity of both complexes was evaluated in vitro. FSA was not adequate as a reducing agent and SnCl2 was better at room temperature than using heat (100 oC). The complexes did not bound well to the bacterias with binding efficiencies ranging from 10 (filtration method) to 16% (centrifugation method). Besides that, a good correlation between colloid formation (impurity) and radioactivity bound to bacterias was found. This decrease in bacterial activity was previously reported in some articles suggesting that quinolones complexed with 99mTc are not suitable to diagnose infections in the presence of inflammation.
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Oh, Herin. "Quinolone resistance in Bacteroides fragilis and Pseudomonas aeruginosa, two opportunistic pathogens /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-498-4.
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Smith, Ashley B. Thornton. "Epidemiology and quinolone-susceptibilities of Salmonella and Campylobacter in feedlot cattle." Diss., Kansas State University, 2017. http://hdl.handle.net/2097/35391.
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Doctor of PhilosophyDepartment of Diagnostic Medicine/Pathobiology
David G. Renter
Salmonella and Campylobacter are two leading causes of human foodborne disease. Cattle can asymptomatically shed these organisms in their feces. Fluoroquinolones are antimicrobials used to treat both humans and animals. With concerns over antimicrobial resistance, antimicrobial use in livestock has become scrutinized. Data on prevalence and susceptibility of Salmonella and Campylobacter in feedlot cattle, particularly those exposed to fluoroquinolones, are sparse. The purpose of the research described in this dissertation was to determine the prevalence and quinolone susceptibility of Salmonella and Campylobacter isolated from feedlot cattle and to determine whether these outcomes were associated with fluoroquinolone use. First, an observational study was performed at five commercial feedlots that used enrofloxacin (a fluoroquinolone) as first-line treatment for bovine respiratory disease (BRD). Fecal samples were collected from cattle pens with various levels of BRD and exposure to enrofloxacin. Salmonella and Campylobacter prevalence and susceptibility to quinolones, nalidixic acid and ciprofloxacin, were evaluated. Prevalence of Salmonella and Campylobacter was highly variable among and within feedlots. All but one Salmonella isolate was susceptible to nalidixic acid and ciprofloxacin, whereas 49% (126/256) of the Campylobacter isolates were resistant to both antimicrobials. However, the number of enrofloxacin treatments was not associated with the prevalence or susceptibilities of either organism. A second, experimental study assessed prevalence and quinolone susceptibilities of Salmonella and Campylobacter in feces of feedlot cattle administered enrofloxacin for the control of BRD (metaphylaxis). Cattle with no history of fluoroquinolone exposure were randomly assigned to either an enrofloxacin treated pen or a non-treated, control pen. Cattle feces were repeatedly collected and cultured for Salmonella and Campylobacter, with isolates tested for susceptibilities to nalidixic acid and ciprofloxacin. Overall, Salmonella and Campylobacter prevalence estimates were relatively low and decreased over time. Resistance prevalence was negligible for Salmonella, but was high for Campylobacter. However, there was no evidence that enrofloxacin metaphylaxis impacted the prevalence of Salmonella or Campylobacter, nor did it significantly affect their susceptibility to human quinolones. In conclusion, enrofloxacin use in feedlot cattle does not appear to have a significant impact on the prevalence or resistance of Salmonella and Campylobacter.
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Feron, Thierry. "Syntheses en serie indolique." Reims, 1997. http://www.theses.fr/1997REIMP202.
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Prothiwa, Michaela [Verfasser]. "Inhibition of Quinolone Biosynthesis in Pseudomonas aerugionsa and Burkholderia species / Michaela Prothiwa." Konstanz : KOPS Universität Konstanz, 2019. http://d-nb.info/1237222036/34.
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Kang, Manjinder S. "Interaction of quinolone antibiotics with the human intestinal CACO-2 cell model." Thesis, Aston University, 2001. http://publications.aston.ac.uk/12354/.
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The transport of a group of quinolone antibiotics across the human intestinal model, Caco-2 cells, was investigated. It was found that the transport of the quinolones generally correlated with the lipophilicity of the compounds, indicating the passive diffusional transcellular processes were involved. However, it was observed that the transport in both directions apical-to-basolateral and basolateral-to-apical was not equivalent, and polarised transport occurred. For all the quinolones studied except, BMS-284756-01, it was found that the basolateral-to-apical transport was significantly greater than the apical-to-basolateral transport. This finding suggested that the quinolones underwent a process of active secretion. The pKas and logPs for the quinolones were determined using potentiometric titrations. The measured logP values were compared with those determined using theoretical methods. The theoretical methods for calculating logP including the Moriguchi method correlated poorly with the measured logP values. Further investigations revealed that there may be an active transporter involved in the apical-to-basolateral transport of quinolones as well. This mechanism was sensitive to competing quinolones, but, it was unaffected by the metabolic inhibitor combination of sodium azide (15mM) with 2-deoxy-D-glucose (50mM). The basolateral-to-apical transport of quinolones was found to be sensitive to inhibition by a number of different inhibitors. The metabolic inhibitors, sodium azide (15mM) with 2-deoxy-D-glucose (50mM) and 2,4-dinitrophenol (1mM), were able to reduce the basolateral-to-apical transport of quinolones. A reduction in temperature from 37°C to 2°C caused an 80-fold decrease in the transport of gatifloxacin in both directions, however, this effect was not sufficient to abolish the greater basolateral-to-apical secretion.
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González, Pinacho Daniel. "Estrategias Analíticas basadas en el Diseño de Inmunoreactivos de Clase para el Control de Residuos de Quinolonas en Leche." Doctoral thesis, Universitat de Barcelona, 2015. http://hdl.handle.net/10803/301432.
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La presencia de contaminantes y residuos químicos en los alimentos es un problema que actualmente genera gran preocupación, ya que presenta importantes implicaciones para la salud y la seguridad pública. En este sentido, el uso indiscriminado, inadecuado y/o fraudulento de fármacos veterinarios puede dar lugar a la presencia de residuos de los mismos en los alimentos de origen animal, entrando de esta forma en la cadena trófica y ocasionando riesgos para la salud. Por otro lado, este tipo de residuos puede ser liberado al medioambiente directamente o indirectamente a través de la utilización del estiércol procedente de animales tratados, generando de esta manera la contaminación de suelos y aguas. En el caso de los antibióticos, la presencia de cantidades residuales en alimentos y en el medioambiente ha sido identificada como una de las causas de la aparición de mecanismos de resistencia a los antimicrobianos por parte de patógenos que causan enfermedades humanas, lo que es motivo de gran preocupación por parte de las autoridades sanitarias, diferentes agencias y organizaciones gubernamentales y de la sociedad en general. Por lo tanto, existe la necesidad de garantizar la seguridad y la calidad de los productos alimenticios, tal es así que los consumidores son cada vez más exigentes, obligando a la industria alimenticia a tener en cuenta sus preocupaciones, en términos de una producción de alimentos más naturales, ecológicos y saludables con un origen claramente rastreable de todos sus ingredientes.
En esta tesis se describe la investigación realizada respecto al desarrollo de técnicas de análisis alternativas que permitan incrementar la eficiencia del control de residuos de antibióticos en alimentos, en base a la utilización de receptores selectivos (anticuerpos). Concretamente, el objetivo final de esta tesis se enfocó al desarrollo de técnicas inmunoquímicas e inmunosensores para la detección de residuos de antibióticos de tipo quinolona en leche. En este sentido, la producción de anticuerpos con selectividad de clase para quinolonas, una de las familias de antibióticos más importante en el ámbito veterinario, ha sido uno de los objetivos principales de este trabajo de investigación. De esta manera, se ha abordado la producción de dichos anticuerpos mediante el diseño racional y síntesis de los haptenos apropiados, utilizando el criterio químico y herramientas de modelización molecular. La evaluación de las características de los anticuerpos generados se ha realizado a través del desarrollo de ensayos de tipo ELISA en microplaca. Los resultados muestran que ha sido posible obtener anticuerpos de clase selectivos para quinolonas, ya que pueden ser detectados hasta diez congéneres de dicha familia con una detectabilidad adecuada para los requerimientos de la Comisión Europea. A su vez, se han desarrollado los protocolos necesarios para la aplicación de estos procedimientos inmunoquímicos al análisis de muestras de leche, estableciéndose un formato semicuantitativo capaz de identificar claramente las muestras libres de quinolona de las contaminadas. Asimismo, los inmunoreactivos y procedimientos inmunoquímicos establecidos se han implementado en un dispositivo inmunosensor amperométrico, basado en la utilización de partículas magnéticas. En este caso, a pesar de la complejidad de la leche, el uso de partículas magnéticas ha permitido la eliminación de las posibles interferencias causadas por los componentes de la matriz, pudiéndose realizar mediciones cuantitativas directamente en muestras de leche, sin ningún tratamiento de muestra adicional o etapa de extracción. Dicho inmunosensor es capaz de detectar hasta siete quinolonas diferentes por debajo de los límites máximos de residuos (LMRs) definidos por el Comisión Europea para la leche, ofreciendo una estrategia prometedora para el análisis in situ, rápido, simple y de bajo costo, de antibióticos de tipo quinolona en muestras complejas.In this thesis, research on the development of alternative analysis techniques increasing the efficiency of the control of antibiotic residues in food is described based on the use of selective (antibodies) receptors. Particulary, the final objective of this thesis was focused to the development of immunochemical techniques and immunosensors for detection of quinolone antibiotic residues in milk. In this sense, the production of class selectivity antibodies for quinolones, one of the most important families in the veterinary antibiotics, has been one of the main objectives of this research. The production of antibodies has been addressed by rational design and synthesis of suitable haptens, by means chemical criteria and molecular modeling tools. The evaluation of the characteristics of the antibodies produced was performed by developing microplate ELISA test. Results show that it has been possible to obtain class selective antibodies for quinolones, able to detected up to ten quinolones with suitable detectability for the requirements of the European Commission. Moreover, protocols for the implementation of these immunochemical methods to the analysis of milk samples have been developed, establishing a semiquantitative format able to clearly identify quinolone free samples from the contaminated. Also, the established immunochemical procedures and immunoreagents developed have been implemented in an amperometric immunosensor device based on the use of magnetic particles. In this case, despite the complexity of the milk, the use of magnetic particles has allowed the elimination of potential interference by matrix components, being able to make quantitative measurements directly in milk samples without any further sample treatment or extraction step. The immunosensor is able to detect up to seven different quinolones below the maximum residue limits (MRLs) established by the European Commission for milk, offering a promising strategy for the in situ, fast, simple and inexpensive analysis of quinolones in complex samples.
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Xiong, Xiaoli. "Structural and biochemical studies of the quinolone resistance protein Qnr from Aeromonas hydrophila." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540907.
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Sreedharan, Santha. "Quinolone resistance in Staphylococcus : role of DNA gyrase and the norA efflux pump." Thesis, St George's, University of London, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267505.
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Ardo, Sandy. "Dégradation oxydative d'une quinolone par la nano-magnétite via l'interaction Fe(II) / O2." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066410/document.
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La magnétite, Fe3O4, est un oxyde de fer naturel à valence mixte Fe(II-III), qui sous sa forme nanométrique, a un fort potentiel d’applications technologiques dans des domaines allant de la biomédecine au traitement des eaux. Les nano-magnétites sont très efficaces pour l’adsorption ainsi que la réduction et l’oxydation de divers polluants environnementaux. Elles peuvent catalyser l’oxydation de type Fenton hétérogène induisant une dégradation efficace des polluants organiques et ceci dans un large domaine de pH. Cependant, les mécanismes impliqués restent mal connus. L’objectif principal de cette étude est d’explorer la capacité de la nano-magnétite à catalyser des réactions radicalaires de type Fenton hétérogène sans ajout d’oxydants forts, mais en utilisant uniquement l’oxygène de l’air. Ces réactions pourraient par la suite constituer la base de nouveaux procédés de remédiation efficace et éco-compatible pour l’élimination des polluants organiques dans différents compartiments de l’environnement. L’acide nalidixique, un antibiotique appartenant à la famille des quinolones, a été utilisé comme contaminant modèle, car ce composé polaire et ionisable se révèle persistant dans l’environnement et récalcitrant aux traitements classiques.Après synthèse de nano-magnétite offrant une surface spécifique élevée, la sorption de l’acide nalidixique sur ce support a été étudiée en conditions anoxiques et une adsorption supérieure à 98 % a été obtenue. En présence d’oxygène, cette sorption est suivie d’une transformation du contaminant modèle. Après désorption selon un protocole qui a été développé, un taux de dégradation d’environ 60 % a été évalué après seulement 30 minutes d’oxygénation, et 80% après 90 minutes. Cinq sous-produits de NAL ont été identifiés par chromatographie liquide couplée à la spectrométrie de masse (UHPLC-MS/MS) et un schéma de dégradation a été proposé. L’analyse de la phase solide par la diffraction des rayons X et par spectroscopie d’absorption au seuil K du fer (XANES et EXAFS) démontre une oxydation significative de la magnétite en maghémite (jusqu’à 40 %). Complétés d’une part par le suivi de la teneur en Fe(II) dissous, et des expériences réalisées en présence d’un piège à radicaux hydroxyles, et d’autres part par l’interprétation des effets du pH et de son évolution lors de la réaction, ces résultats ont permis de proposer un mécanisme réactionnel qui implique la formation des espèces réactives d’oxygène suite à l’oxydation de la magnétite.Les conclusions tirées des résultats expérimentaux prouvent les potentialités prometteuses des oxydes de fer mixte dans la remédiation des sols et eaux contaminés par des composés organiquesMagnetite, Fe3O4, is a natural mixed iron oxide Fe(II-III), that has a wide range of applications in biomedicine as well as in water treatment. Nanosized magnetite presents high capacities to adsorb and transform a wide range of contaminants via oxidative or reductive reactions. It was shown as an active catalyst for heterogeneous Fenton reactions in the removal of organic compounds under a broad range of pH. However, the mechanisms of these reactions are not well defined.The main objective of this study was to explore the nanomagnetite capacity to catalyze heterogeneous Fenton reactions in presence of dissolved oxygen, thus avoiding the use of strong chemical oxidants. These reactions could form the basis of a new efficient and eco-friendly process for the removal of organic pollutants. Nalidixic acid (NAL), an ionizable quinolone antibiotic known for being persistent and recalcitrant to classical treatments, was used as a model contaminant.We synthesized large surface area single-cristalline nanomagnetite with high NAL sorption ability (98%) under anoxic conditions. Furthermore, a desorption protocol was developed to recover the sorbed amount of NAL in order to measure the degradation percentage.Moreover, under oxic conditions, the model contaminant was transformed, up to nearly 60% and 80 % after a 30 and 90 minutes exposure to air bubbling, respectively. Five by-products issuing from the nalidixic acid oxidative degradation were identified by liquid chromatography-mass spectrometry and a degradation pathway was suggested. X-ray powder diffraction and Iron K-edge X-ray absorption spectroscopy were used to investigate mineralogical and iron redox changes in the solid phase over the course of the reaction. Magnetite was oxidized (up to about 40%) into maghemite, -Fe2O3, as the sole product of the oxidation, and without significant change in the size of the particles. These results, in addition to the monitoring of dissolved Fe(II), and experiences conducted in the presence of ethanol as hydroxyl radicals scavenger and at static pH, lead to a better understanding of the reaction mechanism and on the role of pH in the reaction efficiency. In conclusion, this study points out the promising potentialities of mixed valence iron oxides for the treatment of contaminated soils and wastewater by organic pollutants
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Salvaggio, Flavia. "Synthesis of biologically active quinolone natural products extracted from the actinomycete Pseudonocardia sp. CL38489." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648770.
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CHATELUT, LASSALLE MARTINE. "Mise au point d'une technique de bioluminescence pour l'etude de la cinetique de bactericidie de beta-lactamines et quinolones sur pseudomonas aeruginosa." Toulouse 3, 1993. http://www.theses.fr/1993TOU31705.
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Truong, Que Chi. "Resistance aux quinolones par modification de la sous-unite a de la gyrase : role de ces mutations dans la dominance de variants de gyra." Paris 11, 1996. http://www.theses.fr/1996PA114842.
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Ouabdesselam, Saliha. "Aspects genetiques de la resistance aux quinolones chez les bacteries a gram-negatif." Paris 11, 1997. http://www.theses.fr/1997PA114826.
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GAMBART, MARIE-ODILE. "Interet des fluoroquinolones dans le traitement des infections osteo-articulaires ; a propos de 29 observations traitees par ofloxacine." Lille 2, 1989. http://www.theses.fr/1989LIL2M132.
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Pustelny, Christian. "Regulation and quenching of 2-alkyl-4-quinolone dependent quorum sensing in Pseudomonas aeruginosa." Thesis, University of Nottingham, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546515.
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Le, Vien Thi Minh. "Plasmid-mediated quinolone resistance determinants in Enterobacteriaceae isolated in Ho Chi Minh City, Vietnam." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.559782.
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Fluoroquinolones are amongst the most effective antimicrobials used to treat infectious diseases caused by members of the Enterobacteriaceae. The rapid spread of fluoroquinolone resistant Enterobacteriaceae threatens the future effectiveness of this widely used group of antimicrobial compounds. Fluoroquinolone resistance in Enterobacteriaceae in Vietnam highlights an approaching crisis in antimicrobial therapy of Enterobacteriaceae infections as fluoroquinolone resistant infections may require expensive alternative treatments. Furthermore, a lack of alternative drugs for treating fluoroquinolone resistant bacteria also contributes to the difficulty in treating such infections. The aim of this study was to investigate the prevalence and mechanisms of fluoroquinolone resistance in commensal Enterobacteriaceae isolated from two different populations resident in Ho Chi Minh City; hospitalized patients and healthy volunteers. I investigated the prevalence of mutations in the DNA gyrase and the topoisomerase gene, the target of the fluoroquinolones and the main resistance mechanisms in Enterobacteriaceae. Additionally, I investigated the spectrum of plasmid-mediated quinolone resistance (PMQR) determinants, a more contemporary mechanism of fluoroquinolone resistance. By using whole plasmid sequencing, bioinformatics and a miniaturized DNA nanoarray, an association of PMQR determinants with other antimicrobial resistance genes including blaLAP_2, which confers resistance to ~-lactam antimicrobials, was found. Moreover, diverse patterns of antimicrobial resistance between isolates from hospital and community populations were revealed. An increase in the quantity ofPMQR determinants isolated from rectal swabs of children treated with antimicrobials was also demonstrated using a gene specific real-time PCR. I surmise that variety antimicrobial classes might contribute to an increase in copy number and eo- selection of PMQR determinants in Ho Chi Minh City. Fluoroquinolone resistance in Enterobacteriaceae has increased oyer time and this class of antimicrobial is still commonly used, to treat infection caused by such organisms. Understanding fluoroquinolone resistance mechanisms and their relationship to other antimicrobial resistance mechanisms in Enterobacteriaceae should play an important role in the control of the spread of antimicrobial resistance genes and aid treatment strategies for clinicians in Vietnam.