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Quader, Sabina, i N/A. "Selective Synthetic Modification of Aminoglycosides for Drug Targeting to Tuberculosis". Griffith University. School of Biomolecular and Physical Sciences, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20071024.151619.
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The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide. Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.
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Quader, Sabina. "Selective Synthetic Modification of Aminoglycosides for Drug Targeting to Tuberculosis". Thesis, Griffith University, 2007. http://hdl.handle.net/10072/367086.
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The work presented in this thesis details the synthetic modification of the clinically important aminoglycoside antibiotics, neomycin B, paromomycin and tobramycin. We sought to modify aminoglycosides by attaching lipophilic groups, including fatty acids and steroids, with a view to improving the bacterial membrane permeability of these species, and ultimately their efficacy in the treatment of tuberculosis. Our initial synthetic strategy involved direct and specific functionalization of the singular primary hydroxyl group of the aminoglycoside antibiotic neomycin B, with lipophilic groups containing carboxylic acid functions via Mitsunobu esterification. Although, direct and selective Mitsunobu acylation of the primary hydroxyl group proved unsuccessful in the case of the pseudo tetrasaccharide neomycin B, the Mitsunobu reaction did however result in selective chemistry elsewhere in the molecule and this has been exploited for modification of the ido (ring IV) and streptamine (ring II) ring systems. Under carefully controlled conditions, the Mitsunobu reaction has been used for the selective dehydration of the ido ring, to give the talo epoxide, and, under more forcing Mitsunobu dehydration conditions, an aziridine function has been introduced into the streptamine moiety. Both the epoxide and the epoxide-aziridine neomycin building blocks were utilized as synthons in subsequent chemical transformations. Seventeen novel neomycin derivatives featuring modification of ring IV and/or ring II were obtained using this approach. Explicit structural elucidation of all the synthetic intermediates and the final products was achieved using high temperature NMR spectroscopy. Direct and specific functionalization of the singular primary hydroxyl group at the C5 position of the ribose ring (ring III) of neomycin B was achieved, via a procedure based in part on selective tripsylation of the C5III primary hydroxyl group of neomycin B reported previously, followed by subsequent displacement of the tripsyl group by azide.
Terminal alkyne containing lipophilic esters were then successfully attached to the ribose residue of neomycin B via Cu(I)-mediated azide-alkyne coupling reaction. In addition to the isolation of two fortuitous, new and versatile synthons i.e. monoanhydro neomycin and bis-anhydro neomycin for modification of ring IV and ring II of neomycin, a third synthon based on neomycin framework, allowing stepwise modification of ring III and ring IV was designed and synthesized. This synthon features an epoxide function in the ido ring, and a protected amine function at the C5 position of the ribose ring. Examples of the stepwise use of this synthon for further synthetic modification of the neomycin framework were demonstrated. Fourteen novel neomycin derivatives featuring modification of ring III and /or ring IV were obtained and characterized. Regioselective Mitsunobu esterification of the single primary hydroxyl group of the pseudo trisaccharide tobramycin was utilized successfully to link a variety of hydrophobic esters with tobramycin. Nine lipophilic tobramycin derivatives with significant structural diversity were synthesised and characterized. In a preliminary study, the applicability of the Mitsunobu dehydration reaction for the regioselective formation of an epoxide ring in the ido moiety of the pseudo tetrasaccharide aminoglycoside antibiotic paromomycin system was confirmed. The regioselective ring-opening of the derived epoxide with azide at C3IV of paromomycin was also successfully demonstrated. In total, forty-two new potential aminoglycoside antibiotics have been synthesized and characterized.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Faculty of Science, Environment, Engineering and Technology
Full Text
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Sherwin, Catherine M. T., i n/a. "Clinical pharmacology of aminoglycosides in neonates". University of Otago. Dunedin School of Medicine, 2009. http://adt.otago.ac.nz./public/adt-NZDU20090821.160736.
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The aims of this Thesis were to investigate early markers of neonatal sepsis and patient-factors affecting the pharmacokinetics and pharmacodynamics (PKPD) of aminoglycosides in the treatment of neonatal sepsis.
A prospective cohort study of neonates commenced on gentamicin for suspected sepsis was performed between 1 July 2002 and 28 February 2007. Receiver operator characteristics (ROC) plots were used to assess potential markers of sepsis against culture positive sepsis. When sepsis was first suspected, the most promising tests were interleukin (IL) IL-12(p70) with an area under the curve (95% CI) for the ROC of 0.74 (0.63-0.86), and which (with a cut-off at 75 pg/mL) had a sensitivity (95% CI) of 28% (20-36%) and a specificity of 98% (96-100%). IL-10 had a sensitivity of 17% (10-23%) and a specificity of 99% (97-100%).
Retrospective studies of neonates treated with gentamicin, amikacin and netilmicin for suspected sepsis were used to identify patient characteristics that affected aminoglycoside PKPD properties. Population PK modelling used NONMEM� v.5 to determine aminoglycoside clearance (CL) and volume of distribution (V). Logistic regression was used to examine the treatment outcome measures (serum peak and trough concentrations and ototoxicity). Simulations of new dosing regimens were undertaken for netilmicin and amikacin using MATLAB�
The final gentamicin PK covariate model gave CL = 0.097 x (current weight/2)[1.3] x (postnatal age/7)[0.29] and V = 1.07 x (current weight/2)[0.8]+ (confirmed sepsis) x 0.13. A 10% increase in gentamicin V in neonates with sepsis was estimated. For amikacin, 17 (35%) of 49 episodes of confirmed sepsis met the treatment failure criteria from 12 (15%) individual patients. The final amikacin PK covariate model was CL = 0.23 x (current weight/2)[0.691] x (postmenstrual age/40)[3.23] and V = 0.957 x (current weight/2)[0.89]. PD analysis determined risk factors linked to hearing impairment in neonates treated with amikacin included: co-medication with vancomycin, high C-reactive protein concentration and low gestational age. Simulation of a new amikacin dosing regimen recommended: 15 mg/kg 36 hourly, 14 mg/kg 24 hourly, and 15 mg/kg 24 hourly, for neonates [less than or equal to] 28 weeks, 29 to 36 weeks, and [greater than or equal to] 37 postmenstrual age, respectively.
For netilmicin, the final PK covariate model was CL = 0.192 x (current weight/2)[1.35] x (postmenstrual age/40)[1.03], V = 1.5 x (current weight/2)[0.3]. Simulation of a new optimal dosing regimen for netilmicin was: 5 mg/kg 36 hourly, 5 mg/kg 24 hourly, 6 mg/kg 24 hourly, and 7 mg/kg 24 hourly, for neonates [less than or equal to] 27, 28 to 30, 31 to 33, and [greater than or equal to] 34 weeks postmenstrual age, respectively.
IV infusions representing gentamicin administration to neonates of 2.5 kg and 0.5 kg in the NICU setting (30 minutes gentamicin infusion then a 30 minute saline flush) showed the larger neonates received 80% of the drug within 60 minutes. This increased to 90-95% by 75 minutes. However, in extremely low birth weight neonates (0.5 kg), only 60% of the intended gentamicin dose was delivered by 60 minutes (70% by 75 minutes).
In conclusion: IL-12(p70) and IL-10 were identified as promising diagnostic tests to confirm sepsis in neonates. Confirmed sepsis caused a 10% increase in V of gentamicin in neonates, suggesting larger initial dosages (mg/kg) are required for effective treatment of neonates with sepsis. Aminoglycoside clearance in neonates is predominantly affected by current weight, postmenstrual age or postnatal age. Adjusting netilmicin and amikacin doses based on current weight, and dosing interval based on both postmenstrual age and current weight improves drug efficacy. Identification of co-medication with vancomycin, low gestational age, and high C-reactive protein during treatment with amikacin increases risk of hearing impairment. The delivery of gentamicin administrated by IV infusion is substantially extended in extremely low birth weight neonates.
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Buranaphalin, Sawanya. "Pharmaceutical analysis of polyamines and aminoglycosides". Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500693.
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Methods for polyamine derivatization with a panel of extrinsic fluorophores followed by HPLC with fluorescence and UV absorption detection have been developed. Four fluorophores were examined using polyamines and aminoglycosides. o-Phthalaldehyde (OPA) and fluorescamine are selective fluorophores that only react with primary amines; 9- fluorenylmethyl chloroformate (FMOC Cl) and dansyl chloride react with both primary and secondary amines. Reaction and HPLC conditions were optimized with each of the above fluorophores using a series of model mono- and diamines and then applied to natural and semi-synthetic polyamines. The amines that have been investigated are natural di- and polyamines: putrescine, cadaverine, spermidine, spermine, thermospermine, aminoglycosides: kanamycin, paramomycin, neomycin, and synthetic polyamine conjugates e.g. N⁴,N⁹-dioleoylspermine, N¹-cholesteryl spermine carbamate. The resultant derivatives were confirmed by off-line high resolution electrospray ionization mass spectrometry (HR ESI MS). The results show that the synthesis of polyamine derivatives in quantitative yield depends on the time of reaction, the temperature and the ratio of fluorophore reagent. Linearity of derivatization was calculated and regression coefficients ranged from 0.968 to 0.999 with good reproducibility. HR ESI MS analysis of the reaction products demonstrated complete derivatization of both primary and secondary amino groups with dansyl and FMOC fluorescence derivatives and of primary amine groups for OPA and fluorescamine derivatives. Under the ionization conditions used the dansyl derivatives showed, in addition to monovalent ions [M+H]⁺, divalent cations [M+2H]²⁺ because this chromophore contains a basic amine that can be easily protonated. FMOC derivatives gave prominent [M+Na]⁺ ions. The OPA derivatization reaction is rapid, but the products have poor stability. The derivatization with fluorescamine gave multiple products with glucosamine due to the presence of a chiral centre in the fluorophore. The relative quantum yields of the polyaminefluorophore derivatives were examined to determine the effect of intramolecular fluorescence quenching. Dansylation is the fluorescent derivatization method of choice.
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Rayet, Arjinder Kaur. "Analysis of the aminoglycosides neomycin and streptomycin". Thesis, Loughborough University, 1998. https://dspace.lboro.ac.uk/2134/26869.
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The aim of the study was the determination of neomycin and streptomycin aminoglycoside antibiotics in bovine kidney tissue at trace levels. The aminoglycosides contain no chromophore making detection difficult by conventional spectrophotometric detection and are highly polar making separation from tissue samples a multistep clean-up procedure.
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Shrestha, Sanjib K. "Novel Aminoglycosides: Bioactive Properties and Mechanism of Action". DigitalCommons@USU, 2013. https://digitalcommons.usu.edu/etd/2073.
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Fungicide discovery is relatively neglected when compared to the investment in the development of antibacterial, antiviral, and anti-cancer therapeutics. Due to extensive use of currently available fungicides in agriculture and medicine, resistance is emerging among plant and animal pathogenic fungi. This necessitates the search for novel antifungal agents that are effective and less toxic and that do not promote resistance.
FG08 and K20 are novel aminoglycoside analogs synthesized from kanamycin B and A, respectively. The antimicrobial properties of these analogs were tested in vitro against a wide range of agriculturally and clinically important fungal pathogens. Both compounds showed broad-spectrum antifungal properties, but they did not inhibit bacteria such as Escherichia coli and Staphylococcus aureus. The hemolytic activities and cytotoxicities of FG08 and K20 were also evaluated. They showed no toxicity or lowered toxicity against animal cells at their antifungal minimum inhibitory concentrations (MICs).
The fungicidal mechanisms of action of FG08 and K20 were examined using intact cells of Saccharomyces cerevisiae, Cryptococcus neoformans, hyphae of Fusarium graminearum. FG08 and K20 caused SYTOX Green dye uptake and potassium efflux by intact cells, indicating that they increase plasma membrane permeability. FG08 and K20 also caused leakage of pre-loaded calcein from small unilamellar vesicles (SUVs) composed of lipids that mimic the lipid composition of fungal membranes, further suggesting increased membrane permeability as their mechanism of action.
The synergistic interactions of K20 with six azoles (such as itraconazole, and fluconazole) were investigated against a wide array of fungal pathogens. The in vitro results revealed strong synergy between K20 and azoles against plant and human pathogenic fungi. Their synergies were furthered confirmed by time kill curves and disk diffusion methods.
In conclusion, FG08 and K20 are broad-spectrum antifungal agents that do not inhibit bacteria. At their antifungal MICs, they are not toxic to animal cells, but they inhibit fungi by interacting with the fungal plasma membrane, leading to pore formation. These novel aminoglycoside analogs appear attractive for applications as fungicides in agriculture and medicine.
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Xi, Hongjuan. "Thermodynaimic [sic] study of nucleic acids recognition by aminoglycosides". Connect to this title online, 2007. http://etd.lib.clemson.edu/documents/1202499410/.
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Dahl, Russell Scott. "Synthesis of aminoglycosides and amino-C-glycosides from glycals /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2004. http://wwwlib.umi.com/cr/ucsd/fullcit?p3158462.
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Patwardhan, Anjali A. "Mechanistic studies of copper(II) aminoglycoside mediated DNA damage and magnesium catalyzed nuclease activity of hammerhead ribozyme". Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1060971975.
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Thesis (Ph. D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xv, 91 p.; also includes graphics (some col.) Includes bibliographical references (p. 82-91). Available online via OhioLINK's ETD Center
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Pinto, Nelson Schumacher John. "Pharmacokinetics of Amikacin after a single intravenous dose". Auburn, Ala., 2009. http://hdl.handle.net/10415/1848.
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Simon, Binto. "The development of synthetic methodology for stereoselective synthesis of aminoglycosides". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/the-development-of-synthetic-methodology-for-stereoselective-synthesis-of-aminoglycosides(746860dc-9b11-41b9-8283-9201d5149cd9).html.
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RNA is recognised as an important biomolecule involved in many broad cellular functions such as transcription, translation regulation and protein synthesis. Most pathogenic viruses replicate their genome as RNA during some stages in their life cycle. There is an urgent need to develop new methods to treat numerous viral diseases by targeting RNA and to understand the processes by which RNA-protein complexation can be inhibited. Our study focuses on the interactions between the HIV-1 Rev Responsive Element RNA (RRE) with a series of aminoglycosides developed jointly between our group in Manchester and GSK (USA). Even though a number of novel aminoglycoside have been explored previously, they are complex, large molecular weight compounds with low specificity, which limits their use as RNA recognition ligands and anti-viral drugs. The key problem is to be able to synthesise precursors by short, direct routes, avoiding significant detours caused by traditional carbohydrate protecting group strategies, while still delivering sterocontrol and opportunities to diversify. In chapter II we describe our efforts to synthesize the 6-glucosamine moiety (A-ring). A flexible synthesis of 6-aminoglucosamine derivatives can be accomplished in 5 steps using a totally regioselective enzymatic hydrolysis, controlled oxidation to sensitive but manageable aldehydes (hitherto rarely accomplished with a C-4 OAc), and reductive amination technology that allow for unprecedented diversification. In a different approach stereocontrolled synthesis of a model compound was achieved in 4 steps including a novel TEMPO oxidation and a one-pot oxidation/imine-reduction for the complete synthesis of the molecule.Chapter III describes our attempts towards the development of a robust stereoselective O-glycosylation strategy using Lewis acids. In pursuance of an efficient synthesis of our designed RNA binder target compound the stereoselective formation of the glycosidic linkage connecting the A-ring with the 2-DOS ring is an important step. This chapter also gives a general overview of the challenges involved in glycosylation followed by the strategies we employed to overcome some of these issues. We discuss our unusual stereocontrolled glycosylation in which, despite a neighbouring “participatory” group at C-2, the α-glycoside is delivered in high yield. This result implies that the reaction does not occur through a conventional neighbouring group participation.
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Yatchang, Marina Fosso. "Synthesis and Biological Activity of Aminoglycosides and 1,4-Naphthoquinone Derivatives". DigitalCommons@USU, 2012. https://digitalcommons.usu.edu/etd/1371.
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The research described in this dissertation is at the interface of organic chemistry and biology, and it aimed at designing and synthesizing biologically active molecules for the possible development of therapeutic agents. Spinal muscular atrophy is an incurable disease that affects 1 in every 6000 babies, making it the leading genetic cause of infant mortality. While no treatment is available, efforts are being taken to solve this issue. Part of the work outlined in this dissertation was carried out in collaboration with researchers from the University of Missouri to investigate a potential therapeutic for this disease. In addition, the continuous outbreak of diseases caused by bacteria demands for new and improved antibiotics that could help eradicate those pathogens. My research thus allowed me to discover molecules with interesting activity against bacteria for the possible development of potential antibacterial agents. Finally, my research also allowed me to develop potential agro fungicides, which are still very much needed nowadays. Many crop diseases are due to fungal infections,which globally cause enormous economic losses. The use of fungicides is still the main strategy to control these diseases. However, current agro fungicides show some limitations. This is illustrated with Fusarium head blight (FHB), a destructive and costly disease of wheat, barley and other small grains, whose economic losses in the Central United States alone were estimated to $2.7 billion.
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Zimmermann, Louis. "Synthèse et évaluation de dérivés amphiphiles de la néamine et de la néosamine, projet Néa et Néo". Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENV084/document.
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Après la mise en évidence de la forte activité antibactérienne à large spectre contre des bactéries Gram (+) et Gram (-) sauvages et résistantes aux antibiotiques des dérivés 3',4',6-tri-naphtylméthyl (2NM) et -trihexyl d'un petit aminoglycoside, la néamine, et de l'activité, contre les bactéries Gram (+) sauvages et résistantes, des 3',4'- et 3',6-di2NM néamines, les travaux réalisés ont cherché à obtenir des dérivés antibactériens plus actifs et moins toxiques que les dérivés trialkylés. Deux approches en séries aminoglycosides amphiphiles ont été développées dans ce but : (1) la synthèse à partir de la néomycine B de nouveaux dérivés de la néamine portant des groupements alkyles de différentes lipophilies de façon à diminuer globalement celle-ci et (2) après les premiers résultats en série néamine, la synthèse à partir de la N-acétyl glucosamine de dérivés amphiphiles d'un des constituants de la néamine, la néosamine.Dans la première approche, après la mise au point de méthodes d'alkylation de la néamine, il a été possible de passer de dérivés trialkylés de la néamine à des dérivés dialkylés, en particulier 3',6- dialkylés, plus actifs et moins cytotoxiques ceci en diminuant la lipophilie globale des composés. Dans la deuxième approche, à partir de la 1-allyl 3,4-dinonyl néosamine, des dérivés amphiphiles antibactériens à large spectre portant en position anomérique des groupements polaires ont été préparés après époxydation de la double liaison. Le dérivé tri2NM de la néamine s'était avéré avoir une forte affinité pour les lipopolysaccharides de la membrane externe de P. aeruginosa et agir à travers son caractère amphiphiles pour dépolariser la membrane bactérienne. L'étude du mode d'action des dérivés de la néamine préparés les plus actifs a suggéré un mécanisme d'action similaireIn regard to the antibacterial activity of amphiphilic aminoglycosides which are (i) 3',4',6-trinaphtylmethyl (2NM) et -trihexyl neamine derivatives active against wild-type and resistant to antibiotic drugs Gram (+) et Gram (–) bacteria, and (ii) 3',4'- and 3',6-di2NM derivatives active against bacteria Gram (+) bacteria, the works were focused on the search for more active and less toxic derivatives than the trialkyl derivatives. With this aim, two approaches were developed for obtaining antibacterial amphiphilic aminoglycosides: (1) the synthesis from neomycin B of new neamine derivatives carrying alkyl groups of various lipophily in order to decrease the global lipophily and (2) after the first results in the neamine series, the synthesis from N-acetylglucosamine of amphiphilic derivatives of the aminosugar part of the neamine core named neosamine.In the first approach, after optimisation of alkylation methods of neamine, we shifted from active 3',4',6-trialkylated derivatives to less lipophilic more active and less cytotoxic dialkylated derivatives, especially 3',6 derivatives. In the second approach, from 1-allyl 3,4-dinonyl neosamine, large spectrum antibacterial derivatives carrying at the anomeric position polar groups were obtained through epoxidation of the allylic double bond. Previously, the tri2NM neamine derivative has appeared to be able to strongly bind to the lipopolysaccharides of the outer membrane of P. aeruginosa and to destabilize membranes. The study of the mechanism of action of the most active derivatives prepared suggested a similar mode of action
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Gremyachinskiy, Dmitriy. "Total synthesis of aminomethyl c-glycosides". Scholarly Commons, 2000. https://scholarlycommons.pacific.edu/uop_etds/544.
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Chang, Jen-Chieh Jason. "The relative predictive performance of three pharmacokinetic programs for aminoglycosides dosing". Scholarly Commons, 1997. https://scholarlycommons.pacific.edu/uop_etds/2310.
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Commercial pharmacokinetic programs are used to provide clinicians with the tools to predict pharmacokinetic models, estimate pharmacokinetic parameters, and analyze serum data for efficient and consistent drug therapy and, therefore, help clinicians to optimize drug therapy. Many of the commercial programs use different methods of data entry and analysis. In this study, three commercial dosing programs, Kinetidex®, DataKinetics®, and Simkin®, were utilized to evaluate their performance on predicting gentamicin initial dosage regimens and adjusted dosage regimens. The performance of the three programs were compared by measuring the difference in the percentage of the prediction error (PE) as bias and absolute prediction error (APE) as precision using a modified method developed by Sheiner. A clinically significant difference in outcomes was determined to exist if the difference in the calculation of the dosage regimen obtained from the programs as compared to a reference calculated dosage regimen exceeded 1 0 %. A statistically significant difference in the calculation of the dosage regimens obtained from the programs was determined by ANOVA testing (p < 0.05). The results indicated that the Simkin® program had the tendency to overestimate loading doses, and the difference as compared to the reference data was clinically significant. Also the difference observed in calculating loading doses between the Simkin® program and the other two programs was statistically significant. The Kinetidex® program had bias by underestimating daily maintenance doses, and the difference as compared to the reference data was clinically significant. The difference as compared to the reference data for calculating the daily maintenance doses by the DataKinetics® and Simkin® program did not exhibit bias, but the difference was clinically significant. The difference in the performance of predicting daily maintenance doses by the programs was statistically significant in bias but not in precision. The results of computer predicted serum levels versus the measured serum levels indicated that the Kinetidex® program exhibited bias by overestimating the peak and trough concentrations as compared to the other two programs, but there is no statistically significant difference among the programs in precision. In calculating adjusted doses using the measured serum levels, the results obtained from the three programs showed no difference in bias or precision. A comparison of the results of computer-predicted serum levels showed no difference among the programs in bias and precision. In conclusion, the study showed that there was a difference in the predicting ability of the three programs in calculating initial dosage regimens but showed no statistical difference in calculating the total daily-adjusted doses when using patient serum levels.
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McKay, Geoffrey A. "Characterization of aminoglycoside phosphotransferase APH(3')-IIIa : an enterococcal enzyme conferring resistance to aminoglycoside antibiotics /". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0034/NQ66223.pdf.
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Jaunzems, Janis. "Solid-phase assisted synthesis of glycoconjugates, and synthesis of 15N-labelled aminoglycosides". [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968659136.
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Aszodi, Attila. "Études synthétiques dans le domaine des antibiotiques : les anthracyclines et les aminoglycosides". Paris 11, 1988. http://www.theses.fr/1988PA112160.
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Deux domaines de produits naturels sont étudiés: les et les aminoglycosides. La première partie traite des anthracyclines. Afin de effets secondaires de ces dérivés, notamment une forte cardiotoxicité, carbohydrate est remplacé par différents cyclitols. Deux approches vers la synthèse de ces nouveaux ant1cancéreux potentiels ont été mises au point. L'une est basée sur la substitution du groupe en position 7 par un alcoolate. L'autre méthode met en jeu une réaction de DIELS-ALDER. Suivant la nature du diène, l'induction asymétrique varie lors de la réaction de cyclisation. Par cette méthode seule la synthèse sur des modèles simples a pu être réalisée avec de bons rendements, lorsqu’elle a été appliquée à des diènes substitués par un cyclohexane polyfonctionnalisé, les rendements obtenus n'ont pas été satisfaisants. La seconde partie étudie la formation d'un diamlno-1,4 cyclitol, précurseur chiral des fortimicines. La stratégie est la transformation d'un sucre en une cyclohexanone. Celle-ci, après une amination suivie d'une déprotection sélective du site de glycosilation, pourra donner accès aux fortimicinesTwo types of antibiotics were studied in this thesis: anthracyclines and aminoglycosides. The first chapter deals with anthracyclines in which the synthesis of new classes of anthracyclines, hopefully with reduced cardiotoxicity, were attempted. Two approaches were explored:1- Substitution of the benzylic group at position 7 by different alcoholates,2- DIELS-ALDER cycloaddition of a dienophile (epoxytetrone) to a diene bearing chiral cyclohexane substituant. This leads essantially in one step ta the tetracyclic skeleton with a good asymetrie induction. The second chapter deals with the preparation of 1,4-diaminocyclitol which based on a Ferrier rearrangement. The second amine is introduced by oximation follow by reduction
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Akour, Amal. "The role of megalin in the transport of aminoglycosides across human placenta". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/448.
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Background: Intra-amniotic infections (IAIs) are common complications of labor and delivery. If inadequately treated, these infections can lead to significant morbidity and mortality in the mother and the fetus. Intrapartum aminoglycoside (AG) administration is recommended for the management of IAIs. AGs are known to cross the placenta and achieve bactericidal concentrations in fetal serum. However, the highest and most persistent fetal levels are achieved in renal tissue. So, the fetus may be vulnerable to the nephrotoxic effects of AGs. Megalin, a 600 kDaendocytic receptor, is responsible for the uptake of AGs into renal proximal tubular epithelial cells. This receptor is also expressed in human term placenta and it is reasonable to speculate that it is similarly involved in the placental transport of AGs. However, the mechanisms responsible for placental AG uptake and transport have not yet been characterized. Objective: To evaluate the role of megalin in the transport of AGs across human placenta. Specific aims: (1) To assess and compare megalin expression in term and preterm placental villous tissue, and (2) assess the functional activity of megalin in in vitro placental models. Methods: (1) Following IRB approval, placental tissue samples were collected from pregnant women undergoing term or preterm deliveries. Placental villous tissueswere used to quantify megalin expression by western blotting and q-PCR (2) The human choriocarcinoma cell line (BeWo cells) were grown on Transwell plates, and then megalin expression and function were assessed. Results: Megalin protein and mRNA expression were confirmed in samples of human placental villous tissues. Megalin mRNA expression declined steeply with gestational age till week 31 of gestation then it plateaued thereafter. Also, the expression in the early preterm (n=2) was six fold higher than that of both late preterm (n=3) and term placenta (n=10) (p<0.05). The uptake of 3H-gentamicin by the BeWo cells was time-dependent, saturable (Vmax=42.9 ± 4.9 nmol/mg protein/min; Km=2.93±0.68mM) and partially inhibited by megalin inhibitors. Conclusion: Megalin is expressed in human placental villous tissues as well as the BeWo cells. When grown on Transwell® plates, the BeWo cells appear to be the most appropriate model to study the in vitro transport of AGs across the apical membrane. Time, temperature and concentration dependence of gentamicin uptake in the BeWo cells indicate protein-mediated transport. The inhibition data are consistent with megalin-mediated endocytosis of AGs.
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Aszodi, Bernadette. "Etudes synthétiques dans le domaine des antibiotiques les anthracyclines et les aminoglycosides /". Grenoble 2 : ANRT, 1988. http://catalogue.bnf.fr/ark:/12148/cb376114703.
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Alfindee, Madher N. "Synthesis and Biological Studies of Amphiphilic Compounds Derived from Saccharides and Aminoglycosides". DigitalCommons@USU, 2019. https://digitalcommons.usu.edu/etd/7568.
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Adjacent cells communicate through gap junctions (GJs). These GJs are formed by head to head docking of two hemichannels (HCs) from two adjacent cells. HCs are connexin hexamer proteins. Connexin mutation is the most frequent cause of childhood hearing loss. This hearing impairment affects 2 in every 2000 children. Inhibition of the HCs might be the key factor to treat such disorders. A library of amphiphilic kanamycins was synthesized to be tested as HC inhibitors. These compounds showed excellent inhibition activity in comparison with the parent compound (kanamycin A) with less toxicity.
A library of monosaccharide esters with varying carbon chain lengths (acetyl (C2) to hexadecyl (C16)) were synthesized, characterized, and tested for bioactivity. Carbohydrate esters showed low toxicity while remaining active against bacteria and fungi. The compound 6-O-tetradecanoyl-D-mannopyranose (MAN014), a mannose ester with a fourteen-carbon chain, showed the greatest antibacterial and antifungal properties. A mode of action study was tested against Staphylococcus aureus (bacteria) and Fusarium graminearum (fungus) and found the compound perturbed the cell membrum.
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Mugabe, Clement, i Abdelwahab Omri. "La gentamicine sous la forme liposomale : aspects technologique et microbiologique". Acfas-Sudbury, 2005. https://zone.biblio.laurentian.ca/dspace/handle/10219/63.
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Alhariri, Moayad Abdulaziz I. "EVALUATION OF LIPOSOMAL BISMUTH-ETHANEDITHIOL-TOBRAMYCIN FOR TREATMENT OF CYSTIC FIBROSIS PULMONARY PSEUDOMONAS AERUGINOSA INFECTION". Thesis, Laurentian University of Sudbury, 2013. https://zone.biblio.laurentian.ca/dspace/handle/10219/2099.
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The effectiveness of liposomes incorporating bismuth-ethanedithiol and loaded with tobramycin (LipoBiEDT-TOB) at sub-inhibitory concentrations to inhibit the production of quorum sensing signaling molecules and virulence factors induced by P. aeruginosa was evaluated in vitro. In addition, we evaluated the efficacy and safety of free and encapsulated tobramycin in liposomal formulations administered intratracheally to rats chronically infected with P. aeruginosa. LipoBiEDT-TOB significantly reduced the production of quorum sensing signaling molecules and virulence factor secretion compared to free tobramycin. The LipoBiEDT-TOB formulation significantly reduced the bacterial count in lungs, modulated the IL-8 level in blood and minimized the nephrotoxicity that is associated with aminoglycoside treatment. These results support the hypothesis that aerosolization of liposomal aminoglycosides may enhance the management of chronic lung infections caused by resistant P. aeruginosa in patients with cystic fibrosis.
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McKee, Megan, Melanie McLeod i Laura Wicks. "Evaluation of Physicians’ Dosing Procedures for Obese Pediatric Populations and Pharmacokinetics of Aminoglycosides in these Patients". The University of Arizona, 2008. http://hdl.handle.net/10150/624298.
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Class of 2008 AbstractObjectives: This was a retrospective chart review and survey of pediatric residents. This study aimed to examine standards for aminoglycosides in obese pediatrics; increase awareness of drug monitoring in obese populations; and reduce medication errors. Methods: 101 patients aged three to seventeen that received aminoglycoside treatment were included. Subjects were divided into three groups based on weight and height percentiles as defined by growth charts. Collecting retrospective data provided measured concentrations of aminoglycosides in order to evaluate pharmacokinetics. Data collected included: dose and frequency; time dose was given; length of infusion; two measured concentrations (peak and trough); and time concentration was measured. ANOVA allowed comparisons between aminoglycoside volumes of distribution to weight (based on specific weight groups). Tukey’s post hoc analysis further tested the significance of the pair-wise comparisons (p<0.05). Secondly, a questionnaire was administered to 26 pediatric medical residents at University Medical Center to assess current treatment protocols and attitudes towards medication dosing in obese pediatric patients. Results: The volume of distribution was not significantly different between normal weight and overweight patients (p=0.927); normal weight and obese patients (p=0.174); or overweight and obese patients (p=0.211). Most (81.8%) study participants have some difficulty finding references on dosing in overweight and obese patients. Conclusions: The positive correlation between volume of distribution and total body weight was not statistically significant. Pediatric residents agree that there is a lack of resources regarding obese pediatric medication dosing. Further research is warranted to ensure the reliability and validity of aminoglycoside dosing in obese children.
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Mneimneh, Omar. "Evaluation of needs for pharmacokinetic monitoring of aminoglycosides and vancomycin in tertiary hospital". Master's thesis, Lithuanian Academic Libraries Network (LABT), 2007. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2007~D_20070803.122144-66772.
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Background and Objectives: Tendencies in Drug Use (DU) of highly toxic drugs-such as aminoglycosides and vancomycin and level of Rational Drug Use (RDU) is unknown in Lithuania. Our goal was to evaluate the first experiences in serum concentration measurements (Sc) of vancomycin & gentamicin, monitor patients receiving these antimicrobials and explore the practicality of using defined daily dose (DDD) in measuring their consumption tendencies.
Design: DU study based on hospital pharmacy and hospital administrative databases; consumption in DDD per 100 occupied bed daily (100OBD) during 2004-6 and highest consumers of aminoclycosides and vancomycin in 2006. Evaluation of Sc in 2006. Monitoring assessment of 17 patients over 7 months. Data were processed with SPSS 16.0 using descriptive and comparative statistics for nonparametric values (Mann-Whitney test).
Main outcomes measures: Annual consumptions of gentamicin, amikacin, tobramycin and vancomycin according to DDD/100OBD; intensity of gentamicin & vancomycin monitoring (as per number of DDDs) and proportions of abnormal Sc; Evaluation of the rationality level of antimicrobial’s therapy in a cohort of 17 patients.
Results: Mean (±SE) DDD/100OBD values of gentamicin (240mg) were 3.67±0.69 (median 1.31; CI95% 2.29-5.06) in 2004; 4.53±1.87 (median 0.86; CI 95% 0.79-8.27) in 2005, and 4.24±0.82 (median 1.05; CI95%2.60-5.88) in 2006. Mean (±SE) DDD/100OBD values of amikacin (1000mg) were 0.55±0.17 (median 1.22; CI95% 0.23-0... [to full text]Toksiškų vaistų, tokių kaip aminoglikozidų ir vankomicino, bei racionalus vaistų vartojimo tendencijos Lietuvoje dar nėra pakankamai žinomos. Mūsų darbo tikslas buvo nustatyti ir įvertinti aminoglikozidų ir vankomicino suvartojimo KMU klinikose tendencijas , gentamicino ir vankomicino koncentracijas kraujo serume (KKS), bei įvertinti 17 stebėtų pacientų gydymo šiais antibiotikais atvejus. Vaistų suvartojimo duomenys buvo gauti iš ligoninės vaistinės ir jos administracijos. Apskaičiuotos DDD šimtui lovadienių per paskutinius trejus metus (2004 – 2006), nustatyti daugiausia 2006 metais aminoglikozidų ir vankomicino suvartoję KMU klinikų skyriai. Įvertintos 2006 m. antibiotikų KKS. 17 pacientų, gavę šiuos antibiotikus, buvo stebimi 7 mėnesius. Duomenų statistinė analizė buvo atlikta naudojant SPSS 16.0 statistinę duomenų apdorojimo programą, kokybinių duomenų įvertinimui atliktas Mann-Whitney testas neparametriniams kriterijams. Vidutinis gentamicino (240mg) suvartojimas 2004m. (±SE) DDD/100OBD buvo 3.67±0.69 (median 1.31; CI95% 2.29-5.06); 2005m. 4.53±1.87 (median 0.86; CI 95% 0.79-8.27); 2006m. 4.24±0.82 (median 1.05; CI95%2.60-5.88). Amikacino (1000mg) buvo 0.55±0.17 (median 1.22; CI95% 0.23-0.88) 2004m.; 2005m. 0.44±0.13 (median 1.03; CI 95% 0.18-0.69), ir 0.52±0.13 (median 1.08; CI95%0.27-0.78) 2006m. Tobramicino (240mg) buvo 0.03±0.02 (median 0.14; CI95% 0.00-0.07) 2004m, 0.006±0.003 (median 0.03; CI95% 0.00-0.01) 2005m. Vancomicino (2000mg) buvo 0.55±0.17... [toliau žr. visą tekstą]
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Malott, Bradley. "Development and investigation of antibiotic resistance in E. coli using aminoglycosides". Wittenberg University Honors Theses / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=wuhonors1617617698561944.
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Kawasaki, Yukie. "Aminoglycosides and Syringomycin E as Fungicides Against Fusarium graminearum in Head Blight Disease". DigitalCommons@USU, 2008. https://digitalcommons.usu.edu/etd/202.
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Fusarium graminearum is one of the most problematic phytopathogens in US agriculture. This fungus causes head blight, foot rot, and damping off on wheat and barley. The infection lowers the grain yield and causes contamination of the grain product with mycotoxins. Effective control measures are lacking, and new fungicides that kill F. graminearum but remain safe and economical to use are needed. Newly synthesized aminoglycosides (JL22, JL38, JL39, JL40, NEOF004, NEOF005), classic aminoglycosides (amikacin, gentamicin, kanamycin A, kanamycin B, neomycin, and ribostamycin), and a lipopeptide, syringomycin E (SRE), were studied to determine their antifungal potential to control F. graminearum. Aminoglycosides are protein synthesis inhibitors that mainly target bacteria, but a few were recently observed to kill fungi. They consist of an aminocyclitol ring bound with two or more amino sugars. Novel aminoglycosides were recently synthesized using novel glycodiversification synthetic schemes involving the replacement of the original amino sugars with unusual amino sugars. SRE is an antifungal lipodepsinonapeptide produced by Pseudomonas syringae pv. syringae. This bacterium is an opportunistic pathogen in a wide range of plant species and produces several fungicidal lipopeptides. SRE forms pores on fungal plasma membrane and causes ion fluxes. An enhancement of its antifungal activity is reported in the presence of rhamnolipid surfactants. The antifungal activities of various aminoglycosides, SRE, and a SRE-rhamnolipids mixture were determined against F. graminearum by measuring in vitro minimum inhibition concentrations (MICs) and in planta lesion area and chlorosis development using a leaf infection assay protocol. It was determined that using Tween® 20 at 0.2 % (v/v) concentration in the leaf infection assay promotes lesion development by F. graminearum with minimum phytotoxicity. In vitro, SRE, SYRA, and synthetic aminoglycoside JL38 showed the best antifungal activities. With the in planta assay, all three antifungal agents prevented infection by F. graminearum. However, inconsistent phytotoxicities were observed with SRE and SYRA that were influenced by the Tween® 20 surfactant included in the leaf infection assay. How Tween® 20 induces these phytotoxic inconsistencies is not known.
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Lang, Manon. "Un nouveau mécanisme d’entrée des aminosides dans les bactéries Gram-négative". Electronic Thesis or Diss., Sorbonne université, 2023. http://www.theses.fr/2023SORUS143.
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Le nombre de décès dus aux bactéries multirésistantes s'élevait à plus d'un million en 2019, démontrant que la lutte contre les bactéries pathogènes est un enjeu majeur de santé publique. Les aminoglycosides (AGs) sont des antibiotiques à large spectre, efficaces contre les bactéries Gram-négatives grâce à leur capacité à traverser la double barrière membranaire en utilisant la force proton motrice, mais le mécanisme précis reste à élucider. Notre laboratoire a découvert un nouveau mécanisme d'entrée des AGs dans V. cholerae par l'intermédiaire des transporteurs de sucre. Dans cette étude, nous avons montré que la surexpression chez Escherichia coli de plusieurs transporteurs de carbohydrates augmentait la sensibilité aux AGs alors que la délétion d'un seul transporteur avait peu d'impact sur la sensibilité, suggérant une redondance de ces transporteurs capables de se compenser mutuellement et de limiter l'apparition de la résistance. En utilisant un transporteur "preuve de concept" appelé CmtA, nous avons confirmé qu'une entrée différentielle des AGs était lié à la délétion ou la surexpression de ce transporteur. Ce mécanisme est partagé avec d'autres pathogènes, puisque la même sensibilité aux AGs a été observée lors de la surexpression des transporteurs de sucre chez Pseudomonas aeruginosa. Augmenter la production de ces transporteurs en réponse à la présence d'un substrat in vivo pourrait permettre une plus grande efficacité des thérapies aux AGs et une toxicité plus faible, en permettant une meilleure absorption par les bactéries. Nous avons donc cherché un substrat capable d'augmenter l'expression des transporteurs impliqués dans l'absorption des AGs, et nous avons identifié le ribonucléoside uridine comme un activateur. L'ajout d'uridine au milieu de culture permet une plus grande absorption des AGs dans E. coli et n'a pas montré d'apparence de mutant. En mimant une infection des voies urinaires avec un milieu synthétique, l'ajout d'uridine potentialise le traitement par AGs en diminuant la concentration minimale inhibitrice des AGs et en accélérant la cinétique de mort. Nous proposons l'uridine comme potentialisateur du traitement par AG, en co-administrant un AG avec de l'uridine pour stimuler son entrée. Cette étude ouvre la voie à l'amélioration de ces traitements par l'utilisation de carbohydrates pour stimuler l'absorption des molécules AGsThe number of deaths due to multidrug-resistant bacteria was over one million in 2019, demonstrating that the fight against pathogenic bacteria is a major public health issue. Aminoglycosides (AGs) are broad-spectrum antibiotics, effective against Gram-negative bacteria due to their ability to cross the double membrane barrier using the proton motive force, but the precise mechanism remains to be elucidated. Our laboratory has discovered a novel mechanism of entry of AGs into V. cholerae via sugar transporters. In this study, we showed that overexpression in Escherichia coli of multiple carbohydrate transporters increased sensitivity to AGs while deletion of a single transporter had little impact on sensitivity, suggesting a redundancy of these transporters capable of compensating for each other and limiting the development of resistance. Using a "proof-of-concept" transporter called CmtA, we confirmed that differential entry of AGs was linked to the deletion or overexpression of this transporter. This mechanism is shared with other pathogens, since the same sensitivity to AGs was observed upon overexpression of sugar transporters in Pseudomonas aeruginosa. Increasing the production of these transporters in response to the presence of a substrate in vivo could allow for greater efficacy and lower side effects of AG therapies by allowing better uptake by bacteria. We therefore sought a substrate capable of increasing the expression of transporters involved in AG uptake, and identified the ribonucleoside uridine as an activator. The addition of uridine to the culture medium allows for greater AG uptake in E. coli and did not show a mutant appearance. By mimicking a urinary tract infection with a synthetic medium, the addition of uridine potentiates AG treatment by decreasing the minimum inhibitory concentration of AGs and accelerating death kinetics. We propose uridine as a potentiator of GA treatment by co-administering an AG with uridine to stimulate its entry. This study paves the way for improving these treatments by using carbohydrates to stimulate AGs molecules uptake
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Hon, Wai-Ching. "Crystallographic studies on two structures of a kanamycin kinase : a Mg-AMPPNP and a Mg-ADP complex /". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0001/NQ42744.pdf.
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Levy, Jack. "Etude de la résistance aux aminoglycosides chez haemophilus influenzae: incidence, base génétique et mécanisme". Doctoral thesis, Universite Libre de Bruxelles, 1985. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/213662.
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Zhang, Qian. "Synthesis of Flouronogenic Probes for Studying Biomass Degradation and Synthesis of New Antifungal Aminoglycosides". DigitalCommons@USU, 2015. https://digitalcommons.usu.edu/etd/4472.
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This dissertation is composed of two research projects. The first research project is aimed at using synthetic fluorogenic probes to study the possible or dominant linkages in biomass. These probes that mimic the linkages found in lignin-cellulosic biomass are designed to select the optimal fungi from direct evaluation process or could be tested against other microbials to screen candidates which can break ligno-hemicellulose bonds. For the first stage, these probes would be tested against white rot fungi extract. The white rot fungi are used for the first stage to see if releasing or degrading carbohydrates while keeping lignin largely intact is possible or not.
These probes can help to answer fundamental questions, such as what could be the dominant linkages between lignin and hemicellulose, and what are the possible mechanisms for the cleavage of carbohydrates in biomasses. Understanding the linkages in these biomass will enable high efficient degradation or release of carbohydrates, primarily hemicelluloses, from biomass. The second project is focused on synthesizing new aminoglycoside analogs and exploring the potential to revive traditional antibacterial kanamycin as new types of antifungal agents. Aminoglycosides are widely used broad spectrum antibiotics. Although mainly used as antibacterial agents, there have been studies to show amphiphilic aminoglycoside derivatives could be possibly employed as antifungal agents. A concise and novel method for site-selective alkylation of tetra-azidokanamycin has been developed that leads to the divergent synthesis of three classes of kanamycin derivatives. These new amphiphilic kanamycin derivatives bearing alkyl chains length of 4, 6, 7, 8, 9, 10, 12, 14，16 have been synthesized and tested against bacteria and fungi. Surprisingly, the antibacterial effect of the synthesized kanamycin derivatives decline or disappear compared with the original kanamycin A, but some of the compounds show very strong activity as antifungal agents.
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Guyon, Hélène. "Mise au point d'une méthode de mesure d'interaction ligand-ARN par électrochimie". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB147/document.
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Etant donné leur implication dans de nombreux processus biochimiques, les ARN sont maintenant considérés comme des cibles thérapeutiques très prometteuses. Cependant, nos connaissances limitées concernant les phénomènes d'interaction entre les ARN et de petites molécules, compliquent l'élaboration de nouveaux ligands (ou médicaments), capables de reconnaître sélectivement une structure complexe d'ARN. En absence de toute approche rationnelle, une stratégie de criblage pourrait permettre de mieux comprendre ces phénomènes de reconnaissance. Cette thèse porte sur la mise au point d'une méthode électrochimique, simple, adaptée pour du criblage haut-débit et permettant de détecter et de quantifier les interactions ARN/ligands. Le principe de la méthode repose sur la différence de coefficient de diffusion qui existe entre la forme libre d'un ligand possédant des propriétés redox et sa forme complexée à l'ARN. Cette stratégie de détection par voie électrochimique présente comme avantages d'être peu coûteuse, rapide, simple d'utilisation, adaptée pour du criblage haut-débit de molécules et utilisable dans de faibles volumes. Cette méthodologie a été utilisée pour caractériser la formation d'un complexe entre un analogue d'aminoglycoside porteur d'un groupe ferocene et une séquence d'ARNr 16S23. De plus, des expériences de compétition entre le complexe ARN/ligand redox et des aminoglycosides non modifiées permettent d'étendre la méthode à la détermination de constantes de dissociation (KD) pour des molécules non marquées en phase homogène. Ces expériences de compétition pourront être généralisées pour mesurer le KD de librairies de molécules, permettant ainsi de trouver de meilleurs ligands d'ARNRNA molecules play a major role in various biochemical processes and they are now considered as an important drug target. However, our limited understanding of the interactions occurring between small molecules and RNA complicate the search for new ligands (or drugs) with improved specific interaction and binding to elaborated RNA structures. In the absence of any rational approach, a screening strategy could shed light on the ligand/RNA interactions. In this thesis, we describe a simple electrochemical approach allowing for high-throughput detection and quantification of small molecule/RNA interactions. The principle of the method relies on the difference of diffusion rates between a redoxmolecular probe free or bound to its RNA target and thus to the ability to more easily electrochemically detect the forme rover the latter in a homogenous solution. This electrochemical detection strategy has the advantages of being affordable,fast, easy to use, sensitive and well-adapted to a high-throughput screening strategy in small volume samples. This methodology was used to characterize the binding of an aminoglycoside analog bearing a ferocenyl group to the ribosomal RNA fragment (rRNA 16S23). Furthermore, competitive binding of unlabelled aminoglycosides on theRNA/electrochemical probe complex allowed us to evaluate their dissociation constants (KD). These competitive experiments could further be generalized to measure KD values for libraries of molecules, which could help to find better RNA ligands
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Castegren, Markus. "Modulating Organ Dysfunction in Experimental Septic Shock : Effects of Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance". Doctoral thesis, Uppsala universitet, Infektionssjukdomar, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-149274.
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Sepsis is a common diagnose in the intensive care population, burdened with a high mortality. The systemic inflammatory reaction underlying the development of septic organ dysfunction can be modeled using Gram-negative bacterial lipopolysaccharide, endotoxin. This thesis used a porcine endotoxemic experimental sepsis model to address clinical questions difficult to answer in clinical trials; furthermore a model of secondary sepsis was developed. No additional effect on the development of renal dysfunction by tobramycin was found, indicating that a single dose of tobramycin does not further compromise renal function in inflammatory-induced acute kidney injury. Antiendotoxin treatment had no measurable effect on TNF-α-mediated toxicity once the inflammatory cascade was activated. There was an effect on the leukocyte response that was associated with improvements in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure. The lungs stood out compared to the other organ systems as having a threshold endotoxin dose for the protective effect of endotoxin tolerance. As to the development of circulatory and renal dysfunction, tolerance to endotoxin was evident regardless of the endotoxin pre-exposure and challenge dose. There was a temporal variation of endotoxin tolerance that did not follow changes in plasma TNF-α concentrations and maximal tolerance was seen very early in the course. More pronounced endotoxin tolerance at the time of maximum tolerance was associated with a more marked hyperdynamic circulation, reduced oxygen consumption and thrombocytopenia eighteen hours later. It might be of interest to use the experimental model of long-term endotoxemia followed by a second hit, which has been designed to resemble an intensive care setting, for the study of treatment effects of immunomodulating therapies in secondary sepsis.Paper 3, previous title as submitted: "Compartmentalization of organ endotoxin tolerance in a porcine model of secondary sepsis"
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François, Boris. "Cristallographie de complexes entre site de décodage ribosomique et antibiotiques de la famille des aminoglycosides". Université Louis Pasteur (Strasbourg) (1971-2008), 2005. https://publication-theses.unistra.fr/public/theses_doctorat/2005/FRANCOIS_Boris_2005.pdf.
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Bolard, Arnaud. "Identification of novel regulatory pathways involved in non-enzymatic resistance to aminoglycosides in Pseudomonas aeruginosa". Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCE006/document.
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Les antibiotiques sont des molécules incontournables dans le traitement des infections bactériennes. L’émergence et la dissémination de la résistance aux antibiotiques chez la pathogène opportuniste Pseudomonas aeruginosa, ont amené l’Organisation Mondiale de la Santé à déclarer indispensable le développement de nouvelles approches thérapeutiques pour lutter contre cette bactérie. Bien que certaines alternatives aient été envisagées, la préservation de l’activité d’antibiotiques majeurs tels que les aminosides et la colistine est primordiale. La caractérisation des mécanismes de résistance à ces médicaments est nécessaire pour la mise au point de nouvelles molécules et mieux prendre en charge les patients. Dans ce contexte, nous montrons que des mutations dans le gène fusA1 (codant le facteur d’élongation EF-G1A) et dans l’opéron pmrAB (système à deux composants PmrAB) entrainent une augmentation de la résistance aux aminosides chez des mutants isolés au laboratoire et des souches issues de patients, atteints ou non, de mucoviscidose. Certaines substitutions d’acide aminé dans EF-G1A accroissent les niveaux de résistance de 2 à 16 fois aux quatre sous-classes d’aminosides. Par ailleurs, des changements d’acide aminé dans le système à deux composants PmrAB activent l’expression des gènes PA4773-PA4774-PA4775, et la production de norspermidine et de spermidine. La synthèse de ces polyamines va de pair avec une baisse de 4 à 16 fois de la sensibilité aux aminosides à noyan 2-désoxystreptamine bisubstitué en 4,6 (gentamicine, amikacine et tobramycine). De plus, il apparaît que la résistance des mutants pmrB à la colistine est en partie dépendante de la pompe d’efflux MexXY(OprM), un système impliqué dans la résistance naturelle, adaptative ou acquise aux aminosides. Enfin, nous montrons que les mutants pmrB surproduisent des alcaloïdes contenant un motif azétidine, par une voie de synthèse non-ribosomale et dépendante du quorum sensing. Ces alcaloïdes diminuent la virulence de P. aeruginosa dans le modèle Galleria mellonellaAntibiotics are invaluable drugs to combat bacterial infections. Emergence and spread of antibiotic resistance in the opportunistic pathogen Pseudomonas aeruginosa have led the World Health Organization to consider as a crucial priority the development of new therapeutic approaches to fight this bacterium. In addition to other alternatives, preservation of activity of major antibiotics such as aminoglycosides and colistin is primordial. Consequently, characterization of the resistance mechanisms to these drugs is a prerequisite to design novel molecules, and improve patient care. In this context, we show that mutations in gene fusA1 (encoding elongation factor EF-G1A) and in operon pmrAB (two-component system PmrAB) lead to an increased resistance to aminoglycosides in in vitro-selected mutants and strains isolated from cystic fibrosis (CF) and non-CF patients. Certain amino acid substitutions in EF-G1A confer a 2- to 16-fold increased resistance to the four aminoglycoside subclasses. On the other hand, amino acid variations in two-component system PmrAB activate the expression of genes PA4773-PA4774-PA4775, and production of norspermidine and spermidine. This upregulated polyamine biosynthesis is associated with a 4- to 16-fold decreased susceptibility to 4,6-di-substituted deoxystreptamine aminoglycosides (gentamicin, amikacin and tobramycin). Moreover, our work reveals that the acquired resistance of pmrB mutants to colistin partially depends upon pump MexXY(OprM), a system that otherwise mediates intrinsic, adaptive and acquired resistance to aminoglycosides. Finally, we show that pmrB mutants overproduce azetidine-containing alkaloids by a quorum-sensing-regulated, nonribosomal peptide synthetase pathway. These alkaloids impair the virulence of P. aeruginosa in a Galleria mellonella infection model
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Bugaud, Olivier. "Suppression traductionnelle des codons stop chez les mammifères". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS222.
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Entre 10% et 30% des maladies humaines sont liées à l'apparition d'une mutation non-sens (PTC). La synthèse protéique est alors arrêté prématurément. Cet arrêt peut être inhibé par des molécules inductrices de translecture qui permettent l’incorporation d’un ARNt suppresseur naturel au niveau du PTC (translecture). Le ribosome peut alors franchir le PTC et restaurer l’expression de la protéine.Au cours de ma thèse, je me suis intéressé à la suppression des codons stop en caractérisant de nouvelles molécules inductrices de translecture et en analysant les mécanismes de la fidélité de la traduction.J’ai tout d’abord mis au point un système de criblage innovant avec lequel j’ai testé plus de 17 000 molécules et identifié la molécule TLN468. J’ai pu mettre en évidence que cette molécule est capable d’induire la réexpression d’une protéine p53 active.J'ai aussi caractérisé de nouveaux composés dérivés d’aminoglycosides. J’ai pu montré que le NB124 est capable d’induire l’apoptose de cellules tumorales via la réexpression de la protéine p53 tout ayant une toxicité bien plus faible que la gentamicine.En parallèle, j’ai développé une approche en molécule unique permettant d’étudier les erreurs programmées du ribosome (recodage). J’ai ainsi pu analyser la cinétique d’élongation des ribosomes eucaryotes et montré que l’initiation de la traduction sur un site d’entrée interne (IRES) ralentit le ribosome lors des premiers cycles d’élongationNonsense mutations, also known as premature termination codons (PTCs) are responsible for 10% to 30% of all human genetic diseases. Nonsense translation suppression can be induced by readthrough inducers. The presence of such PTC leads to premature translation termination. These stop therapeutic strategies have emerged which attempt to use molecules that facilitate tRNA incorporation at the PTC (readthrough). The, translation continue in the same reading frame until the next stop codon. I first developed an innovative screening system I used to test more than 17,000 molecules and have identified one hit, TLN468 molecule. I have shown that this molecule is able to induce re-expression of an active p53 protein.I also characterized new compounds derived from aminoglycosides. I have shown that the NB124 induces apoptosis of tumor cells by re-expressing p53 protein while having a much lower toxicity than gentamicin.I developed a single molecule approach for studying the ribosome programmed errors (recoding). I was able to analyze the kinetics of elongation eukaryotic ribosomes and showed that the initiation of translation at an internal entry site (IRES) slows the ribosome during the first elongation cycle
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BUGNON, DENIS. "Methode de simulation de la pharmacocinetique humaine chez l'animal : nouvelle technique et son application aux aminoglycosides". Nantes, 1991. http://www.theses.fr/1991NANT120M.
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Rudolph-Claasen, Zerilda Suzette. "Hearing loss amongst DR-TB patients that have received extended high-frequency pure tone audiometry monitoring (KUDUwave) at three DR-TB decentralized sites in Kwazulu Natal". University of the Western Cape, 2018. http://hdl.handle.net/11394/6583.
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Magister Public Health - MPHOtotoxic induced hearing loss is a common adverse event related to aminoglycosides used in Multi Drug Resistant -Tuberculosis treatment. Exposure to ototoxic drugs damages the structures of the inner ear. Symptomatic hearing loss presents as tinnitus, decreased hearing, a blocked sensation, difficulty understanding speech, and perception of fluctuating hearing, dizziness and hyperacusis/recruitment. The World Health Organization (1995) indicated that most cases of ototoxic hearing loss globally could be attributed to treatment with aminoglycosides. The aim of the study was to determine the proportion of DR-TB patients initiated on treatment at three decentralized sites during a defined period (1st October to 31st December 2015) who developed ototoxic induced hearing loss and the corresponding risk factors, whilst receiving audiological monitoring with an extended high frequency audiometer (KUDUwave). A retrospective cross-sectional study was conducted. Cumulatively across the three decentralized sites, 69 patient records were reviewed that met the inclusion criteria of the study. The mean age of the patients was 36.1, with a standard deviation (SD) of 10.7 years; more than half (37) were female. Ototoxicity , a threshold shift, placing patients at risk of developing a hearing loss was detected in 56.5% (n=39)of patients and not detected in 30.4%(n=21).The remaining 13,1% (n=9)is missing data. As a result, the regimen was adjusted in 36.2% of patients. . From the 53 patients who were tested for hearing loss post completion of the injectable phase of treatment, 22.6% (n=12) had normal hearing, 17.0 % (n=9) had unilateral hearing loss, and 60.4% (n=32) had bilateral hearing loss. Therefore, a total of 41 patients had a degree of hearing loss: over 30% (n=22)had mild to moderate hearing loss, and only about 15% (n=11)had severe to profound hearing loss. Analysis of risk factors showed that having ototoxicity detected and not adjusting regimen significantly increases the risk of patients developing a hearing loss. The key findings of the study have shown that a significant proportion of DR-TB patients receiving an aminoglycoside based regimen are at risk of developing ototoxic induced hearing loss, despite receiving audiological monitoring with an extended high frequency audiometer that allows for early detection of ototoxicity (threshold shift).
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Hunt, Kevan Owen. "An epidemiological study in the greater Durban area of gram negative bacilli resistant to aminoglycoside antibiotics". Thesis, Cape Technikon, 1998. http://hdl.handle.net/20.500.11838/2254.
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Thesis (MTech (Medical Technology))--Cape Technikon, 1998.This study was undertaken to investigate resistance to aminoglycoside antibiotics and the transfer of resistance in selected Gram negative bacilli in hospitals in the Greater Durban area in order to determine whether the development of resistance in this region was similar to that found in other countries and whether it was the same in the hospitals in the region. It was intended that the study might expose the existence of nosocomial pathogens of a particular strain or endemic plasmids responsible for aminoglycoside antibiotic resistance. Strains of Klebsiella, Enterobacter and Serratia species and Escherichia coli resistant to gentamicin, tobramycin, netilmicin or amikacin were obtained. Resistance of the isolates obtained to the above aminoglycoside antibiotics was confirmed using a disc diffusion technique. Resistance mechanisms were initially assigned on the basis of resistance to these four aminoglycoside antibiotics. In approximately 50% of the isolates, including donor isolates and their respective transconjugants, resistance mechanisms were confirmed or revised on the basis of a changed resistance profile to a range of 12 aminoglycoside antibiotics in conjunction with DNA/DNA hybridization tests. Bacterial conjugation studies were performed on selected isolates to investigate the transfer of aminoglycoside resistance from Klebsiella pneumoniae isolates to recipient Escherichia coli. Plasmid profiles of all isolates and Escherichia colitransconjugants were compared to establish similarities. Isolates in three of the four genera of bacteria and all isolates collectively, demonstrated the greatest incidence of resistance to tobramycin. Amikacin resistance was, in all groups of isolates, the least frequently encountered. Collectively, the most frequent mechanisms of resistance were the AAC(3)-V and AAC(6')-1 enzymes One large hospital showed a high frequency of the AAC(3)-V modifying enzyme while in other hospitals a wider range of enzyme resistance mechanisms were evident. Plasmid profiles were generally dissimilar within and between different genera and the different hospitals.
Mangosuthu Technikon Research Fund
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Geyer, Lúcia Bencke. "Limiares auditivos em altas frequências e emissões otoacústicas em pacientes com fibrose cística". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/98476.
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Introdução: O tratamento dos pacientes com fibrose cística envolve o uso de medicamentos ototóxicos, sendo que os mais frequentemente utilizados são os antibióticos aminoglicosídeos. Devido ao uso frequente deste tipo de medicamento, os pacientes com fibrose cística apresentam risco de desenvolver perda auditiva. Objetivo: o objetivo deste estudo foi avaliar a audição dos pacientes com fibrose cística pela audiometria de altas frequências (AAF) e emissões otoacústicas por produto de distorção (EOAPD). Pacientes e métodos: estudo transversal retrospectivo e prospectivo, incluindo 75 indivíduos, sendo 39 do grupo de estudo e 36 do grupo controle. Foram realizados os exames de AAF (de 250 a 16.000 Hz) e EOAPD. Resultados: o grupo de estudo apresentou limiares na AAF significativamente mais elevados em 250, 1.000, 8.000, 9.000, 10.000, 12.500 e 16.000 Hz. (p=0,004) e maior prevalência de alterações nas EOAPD em 1.000 e 6.000 Hz (p=0,001), com amplitudes significativamente mais baixas em 1.000, 1.400 e 6.000 Hz. Houve associação significativa entre as alterações dos limiares auditivos na AAF com o número de cursos de aminoglicosídeos realizados (p=0,005). Oitenta e três por cento dos pacientes que realizaram mais de 10 cursos de aminoglicosídeos apresentaram perda auditiva na AAF. Conclusão: Um número expressivo de pacientes com fibrose cística que receberam repetidos cursos de aminoglicosídeos apresentou alterações na AAF e EOAPD. realização de 10 ou mais cursos de aminoglicosídeos esteve associada às alterações na AAF.Introduction: the treatment of patients with cystic fibrosis involves the use of ototoxic drugs, and the most frequently used are the aminoglycoside antibiotics. Due to the frequent use of this drug, cystic fibrosis patients are at risk to develop hearing loss. Objective: the aim of this study was to evaluate the hearing of patients with cystic fibrosis by high frequency audiometry (HFA) and distortion product otoacoustic emissions (DPOAE). Patients and methods: retrospective and prospective crosssectional study including 75 individuals, 39 of the study group and 36 in the control group. HFA (250 – 16,000 Hz) and DPOAE tests were conducted. Results: the study group had thresholds significantly higher in the HFA in 250, 1,000, 8,000, 9,000, 10,000, 12,500 and 16,000 Hz (p=0.004) and higher prevalence of abnormal DPOAE at 1,000 and 6,000 Hz (p=0.001), with significantly lower amplitudes of 1,000, 1,400 and 6,000 Hz. There was a significant association between changes in hearing thresholds in HFA with the number of courses of aminoglycosides performed (p=0.005). Eighty-three percent of patients who completed more than 10 courses of aminoglycosides had hearing loss in HFA. Conclusion: a significant number of patients with cystic fibrosis who received repeated courses of aminoglycosides showed alterations in HFA and DPOAE.
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Pothayee, Nikorn. "Development of Core-Shell Polymeric Nanostructures for Delivery of Diagnostic and Chemotherapeutic Agents". Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/77286.
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Macromolecular complexes of anionic-nonionic block copolymers and cationic antibiotic aminoglycosides have been formed by electrostatic condensation. Amphiphilicity of the complexes was introduced into the shells by incorporating a hydrophobic poly(propylene oxide) segment into the block copolymer. The resulting particles have an average hydrodynamic diameter of ~ 200 nm and contain up to 30-40 % of the drug payload. In vitro efficacies of such nanostructures in reduction of intracellular pathogens like Salmonella, Listeria, and Brucella were demonstrated. Current effort focuses on translation of this nano-drug delivery concept to in vivo model of intracellular infectious diseases.
Atom transfer radical polymerization (ATRP) was utilized to prepare well-defined polymeric dispersion stabilizers that readily adsorb onto metal oxide surfaces. Two unimolecular bis(phosphonate) ATRP initiators were designed and prepared in good yield. These special initiators were successfully used to initiate polymerization of poly(N-isopropylacrylamide) (PNIPAM) in a controlled manner yielding PNIPAM with a bis(phosphonate) moiety at one terminus. The polymers readily adsorbed onto magnetite nanoparticle surfaces, thus creating thermosensitive magnetic nanostructures that form nanosized clusters upon heating above the lower critical solution temperature of PNIPAM. It is envisioned that modularity of this approach, relying on the applicability of ATRP to polymerize a vast array of monomers, could be used to prepare a library of polymeric shells for magnetic iron oxide nanoparticles.
Medical intervention in drug delivery that includes detectability of drug carriers is greatly desirable. A real-time assessment of disease prognosis could be highly beneficial for developing personalized treatment strategies. As an example of this conceptual innovation, block ionomer functionalized magnetite complexes were synthesized and investigated as carriers for delivery of aminoglycosides into phagocytic cells for treatment of intracellular bacterial infections. The ionic block of copolymer contains multiple carboxylates for binding onto the iron oxide surface. The remaining unbound carboxylate anions were used to complex with cationic gentamicin in nanoshells of these complexes. The iron oxide particle core provides an imaging modality and serves as a pseudo-crosslinking site to enhance stabilities of the polyelectrolyte complexes, thus preventing them from disintegrating in the physiological environment. Currently, these hybrid complexes are being investigated in possible pharmaceutical formulations to eradicate intracellular pathogens in animal models.Ph. D.
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Heffernan, Aaron J. "Dose optimisation of intravenous and nebulised antibiotics for the treatment of Pseudomonas aeruginosa pneumonia". Thesis, Griffith University, 2023. http://hdl.handle.net/10072/421611.
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Ventilator-associated pneumonia remains commonplace in critically ill patients and is associated with an increased morbidity and mortality. Multidrug-resistant Gram-negative bacillary pathogens, such as Pseudomonas aeruginosa, are commonly implicated in the pathogenesis of ventilator-associated pneumonia. Increasing rates of antibiotic resistance have led to increasing interest in repurposing old antibiotics with alternative administration methods and the development of new antibiotics that have activity against these multidrug-resistant isolates. Moreover, ensuring that the optimal dose is used is of paramount importance to improve patient outcomes and prevent resistance emergence to these novel antibiotic therapies.
Amikacin, an aminoglycoside antibiotic, is of interest in the management of ventilator-associated pneumonia given that it retains activity in up to 70% of multi-drug resistant P. aeruginosa isolates. However, amikacin penetrates poorly into the infection site in patients with ventilator-associated pneumonia, resulting in subtherapeutic exposures when administered intravenously. Therefore, there has been renewed interest in dosing for innovative administration methods, such as inhaled dosing for direct drug delivery to the site of infection. Alternatively, new agents such as ceftolozane/tazobactam, have been developed and are increasingly used clinically, particularly for multidrug-resistant P. aeruginosa. However, a paucity of pharmacodynamic studies exist to assist clinicians with prescribing a dose that both increases the probability of treatment success and minimises the emergence of resistance.
Therefore, the primary aims of this thesis are to describe the infection site pharmacodynamics of amikacin and ceftolozane/tazobactam against P. aeruginosa, to determine the likely dosing strategies for both agents that will achieve maximal bacterial killing and minimise the risk of resistance emerging. A series of in vitro studies and in silico simulations are used to describe the impact of different dosing regimens on bacterial killing and emergence of resistance.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medicine & Dentistry
Griffith Health
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Lombès, Thomas. "Synthèse d’analogues d’aminoglycosides par voie chimique et ingénierie métabolique : Application à l’étude des ARN par RMN du fluor". Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T044/document.
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Les ARN constituent des cibles thérapeutiques extrêmement intéressantes bien qu’encore assez peu exploitées. En effet, les obstacles pour la conception de ligands spécifiques de ces cibles non traditionnelles, polyanioniques et très flexibles, sont encore loin d’être levés. Les aminoglycosides, utilisés depuis longtemps pour leurs propriétés antibiotiques, sont souvent décrits comme des « ligands universels » d’ARN. Leur structure constitue donc une architecture favorable pour l’élaboration de nouveaux ligands spécifiques des ARN.Le but de cette thèse a été de développer une méthode systémique originale combinant chimie organique et microbiologie pour synthétiser de nouvelles molécules de structure analogue aux aminoglycosides, se fixant de façon spécifique sur des cibles ARN. Ce travail repose sur la compréhension récente des voies de biosynthèse des aminoglycosides permettant leur ingénierie rationnelle selon une stratégie de mutasynthèse. Cette approche expérimentale s’appuie sur la conception de mimes de métabolites naturels pouvant être transformés par des bactéries génétiquement modifiées. Le développement de méthodologies novatrices en ingénierie métabolique, synthèse organique et chimie analytique nous a permis de concevoir des analogues d’aminoglycosides fluorés qui se sont avérées être d’excellentes sondes dans l’étude des ARN par RMN du fluorPas de résumé en anglais
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RUZAFA, ISABELLE. "Aminoglycosides en pathologie infectieuse respiratoire severe : etude de l'efficacite et de la tolerance de l'amikacine en mono-dose quotidienne chez 27 patients". Toulouse 3, 1992. http://www.theses.fr/1992TOU31118.
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SOUZA, CABRINI FERRAZ DE. "DEVELOPMENT OF CAPILLARY ELECTROPHORESIS BASED METHODS WITH DIFFERENT DETECTION APPROACHES FOR DETERMINATION OF ORGANOTINS, STROBILURINS AND AMINOGLYCOSIDES". PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO, 2013. http://www.maxwell.vrac.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=23181@1.
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PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIROCOORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIOR
CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO
PROGRAMA DE EXCELENCIA ACADEMICA
Neste trabalho, métodos baseados em diferentes abordagens em eletroforese capilar (CE) foram propostos. No caso da determinação de compostos organoestanhos ou OTs (difenilestanho e monofenilestanho) em fluidos biológicos, foi usada abordagem de eletroforese capilar por zona (CZE) hifenada com a espectrometria de massas (do tipo quadrupolo) com fonte de plasma indutivamente acoplado (CE-ICP-MS). As condições de análise foram estudadas no modo univariado visando otimizar a composição da solução eletrolítica (tampão acetato 5,0 mmol L(-1), pH 2,8) e obter os parâmetros instrumentais (45 graus Celsius, mais 30 kV e 30 s de tempo de introdução hidrodinâmica de amostra). A solução de complementação foi uma solução aquosa 5,0 mmol L(-1) de NH4NO3 contendo 10 por cento metanol em volume e 1,0 Mg L(-1) de Cspositivo, com pH ajustado para 2,8 com tampão acetato. A vazão dessa solução foi mantida em 40 ML min(-1). Os OTs foram diluídos em solução de metanol:tampão acetato de sódio 50:50 por cento v/v ou apenas em tampão acetato de sódio pH 2,8. As condições de detecção do ICP-MS foram ajustadas em 1200 W, 15 L min(-1) de vazão de argônio para formação do plasma, 1 L min(-1) de vazão de argônio auxiliar. A vazão de argônio do nebulizador foi ajustada diariamente. Os isótopos de estanho 120Sn e 118Sn foram monitorados, assim como o 133Cspositivo para controlar a eficiência e estabilidade do processo de nebulização. A resposta linear do método ficou entre 0,050 a 2,0 mg L(-1) de Sn (0,42 a 17 Mmol L-(1)). Os limites de detecção (LOD) e de quantificação (LOQ) em termos de Sn foram de 15 Mg L(-1) (0,13 Mmol L(-1)) e 50 Mg L-1 (0,42 Mmol L(-1)), calculados utilizando a menor concentração dos picos dos analitos que podem ser diferenciados do sinal de fundo. A repetibilidade para o tempo de migração e área dos picos ficou próximo a 5 por cento. O método foi aplicado na análise de urina, sangue total e plasma fortificados com os OTs. Recuperações entre 75 e 95 por cento foram obtidas. No caso da determinação de sete pesticidas da classe das estrobilurinas (azoxistrobina, 9 dimoxistrobina, fluoxastrobina, picoxistrobina, piraclostrobina, trifloxistrobina e kresoxim-metil) em sopas infantis, foi usada a cromatografia eletrocinética capilar micelar (MEKC) com detecção fotométrica (no UV) com capilar de caminho óptico estendido. Um estudo multivariado, usando um planejamento 33 Box Behnken, indicou que a melhor separação para os pesticidas foi com solução aquosa de eletrólito composto por tampão tetraborato de sódio (5,1 mmol L(-1), pH 9,0) contendo 51 mmol L(-1) de dodecil sulfato de sódio (SDS) e 24 por cento acetonitrila (ACN) em volume. As condições instrumentais foram 25 C e mais 30 kV de diferença de potencial aplicada, 45 s de tempo de introdução hidrodinâmica de amostra e detecção em 210 nm. Para aumentar o poder de detecção, foi usada a concentração dos analitos no capilar. Para tal, as soluções de padrões e amostras foram dissolvidas em solução tampão tetraborato de sódio 45 mmol L(-1): acetonitrila 80:20 por cento v/v. As curvas analíticas apresentaram comportamento linear e os valores de LOD ficaram entre 7,0 Mg L(-1) ou 18 nmol L(-1) (piraclostrobina) a 15 Mg L-1 ou 33 nmol L(-1) (fluoxastrobina). Os valores de LOQ ficaram entre 21 Mg L(-1) ou 54 nmol L(-1) (piraclostrobina) a 45 Mg L(-1) ou 98 nmol L(-1) (fluoxastrobina). A repetibilidade ficou entre 1,7 a 7,9 por cento para a área de pico e entre 0,25 a 0,71 por cento para o tempo de migração. A precisão intermediária, avaliada com análises realizadas em diferentes dias, apresentou valores entre 1,3 a 5,3 por cento para a área de pico e entre 0,06 a 0,90 por cento para o tempo de migração. O método foi aplicado na análise de sopas prontas infantis fortificadas com as estrobilurinas. Os pesticidas foram extraídos aplicando o método QuEChERS com ajuste de pH com tampão acetato e limpeza com extração em fase sólida dispersiva. Os resultados das análises obtidos c
In this work, analytical methods based on different approaches using capillary electrophoresis (CE) have been proposed. For the determination of organotins or OTs (diphenyltin and monophenyltin) in biological fluids, the separation using capillary zone electrophoresis (CZE) was applied using tandem with inductively coupled plasma mass spectrometry (CE-ICP-MS). The conditions for the analysis were optimized in an unvaried way aiming to find the conditions for the electrolyte solution (acetate buffer, 5.0 mmol L (-1), pH 2.8) and the employed instrumental parameters (45C, 30 kV and 30 s of the time for hydrodynamic introduction of the sample). A complementary solution was composed by NH4NO3 5.0 mmol L(-1), 10 por cento v/v of methanol and 1.0 g L(-1) of Cspositive in acetate buffer with pH adjusted to 2.8. The flow of this solution was set to 40 ML min(-1). The OTs were diluted either in a methanol: acetate buffer 50:50 por cento v/v solution or only in sodium acetate buffer pH 2.8. The conditions for detection by ICP-MS were set to 1200 W, 15 L min(-1) for the Ar plasma flow and 1,0 L min(-1) for the auxiliary Ar. The nebulizer Ar flow was adjusted daily. The monitored tin isotopes were 120Sn 118Sn. The isotope 133Cs was also monitored in order to control the efficiency and stability of the nebulization. The method presented a linear response between 0.05 and 2.0 mg L(-1) (0.42 a 17 Mmol L(-1)) for Sn. The value for the limits of detection (LOD) and for the limits of quantification (LOQ) for Sn were 15 Mg L(-1) (0.13 Mmol L-1) e 50 Mg L(-1) (0.42 Mmol L(-1)), calculated based on the lowest concentration of the analyte peaks that can be differentiated from the background signal. The repeatability for migration time and peak area was approximately 5 per cent. The method was applied in the analysis of organotin fortified blood and urine samples with recoveries between 75 and 95 per cent. In the case of the determination of seven strobilurin class pesticides (azoxystrobin, dimoxystrobin, fluoxastrobin, picoxystrobin, pyraclostrobin, trifloxystrobin and kresoxim-methyl) in baby food (vegetable and fruit soups), 12 the micellar electrokinetic capillary chromatography (MEKC) was used using photometric detection (UV) in a capillary with extended optical path. A multivariate study, with 33 Box Behnken design, indicated the best composition for the electrolytic solution to separate the seven pesticides: a sodium tetraborate buffer (5.1 mmol L(-1), pH 9.0) solution containing 51 mmol L(-1) sodium dodecyl sulfate and acetonitrile (24 por cento in volume). The instrumental conditions were 25C, 30 kV of applied voltage, 45 s for hydrodynamic introduction of the sample and detection at 210 nm. To increase the detection power, the concentration of the analytes into the capillary was used by using the Normal Stacking Mode. For this purpose, the solutions of standards and samples were prepared in 45 mmol L(-1) sodium tetraborate buffer solution: acetonitrile 80:20 por cento v/v. The analytical curves presented a linear behavior and the LOD values were between 7.0 Mg L (-1) or 18 nmol L(-1) (pyraclostrobin) to 15 Mg L(-1) or 33 nmol L(-1) (fluoxastrobin). The LOQ values were between 21 Mg L(-1) or 54 nmol L(-1) (pyraclostrobin) a 45 Mg L(-1) ou 98 nmol L(-1) (fluoxastrobin). The repeatability was between 1.7 to 7.9 por cento for the peak area and between 0.25 to 0.71 por cento for the migration time. The intermediate precision, evaluated by the analysis performed in different days were between 1.3 to 5.3 por cento for the peak area and between 0.06 and 0.90 per cent for the migration time. The method was applied in the analysis of baby food spiked with strobilurin. Pesticides were extracted using the QuEChERS method with pH adjustment with acetate buffer and clean-up using the dispersive solid phase extraction. The analysis results were statistically identical to those obtained with a chromatographic method adapted from the literature. The CZE separation mode was chosen to evaluate the potential of the indirect determination of ami
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Pradier, Léa. "Une approche éco-évolutive de la propagation de la résistance antibiotique : l'exemple de la résistance aux aminoglycosides". Thesis, Université de Montpellier (2022-….), 2022. http://www.theses.fr/2022UMONG014.
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Face à la pression des antibiotiques de nombreux mécanismes de résistances existent. Ces derniers représentent un problème de santé publique qui a et va avoir des conséquences importantes sur la mortalité humaine. Malgré diverses stratégies — principalement basées sur la réduction de la consommation d'antibiotiques — ce problème persistant peine à être contenu. De plus, même s'il est indéniable que l'utilisation massive d'antibiotiques au cours des dernières décennies a été un moteur de l'évolution de la résistance aux antibiotiques, son impact sur l'émergence et la propagation de la résistance aux antibiotiques est souvent surestimé par rapport à d'autres facteurs. Premièrement, la sélection sur la résistance aux antibiotiques ne peut pas être limitée aux antibiotiques à usage humain. Deuxièmement, l'évolution (c'est-à-dire l'émergence, le maintien et la diffusion) d'un trait dans une population repose également sur d'autres forces évolutives et processus écologiques. Enfin, l'entrelacement de ces facteurs résulte en une évolution complexe du phénotype résistant, dépendante de plusieurs échelles allant du déterminisme génétique aux dynamiques environnementales. L'objectif de cette thèse est donc, en s'appuyant sur une approche éco-évolutive, d'améliorer la compréhension des forces et des mécanismes qui façonnent les directions et le mouvement des gènes de résistance aux antibiotiques. Pour ce faire, cette thèse se concentre sur la résistance aux aminoglycosides par le biais d'enzymes d'altération. Les résultats de ces travaux mettent en évidence l'importance des facteurs écologiques et génomiques dans la circulation des gènes de résistance, et concluent ainsi à la nécessité d'études intégratives de la résistance. Dans un premier temps, cette thèse révèle que la distribution de la résistance aux aminoglycosides n'est que très peu liée aux variations de consommation d'aminoglycosides en Europe, mais fortement structurée par la mondialisation (commerce, migration) et plus encore par la connectivité écologique. Une analyse ultérieure souligne le rôle sous-estimé des bactéries non pathogènes dans le transfert horizontal des gènes de résistance aux antibiotiques à grande échelle phylogénétique. A la lumière de ces résultats, cette thèse propose des pistes de réflexion sur l'étude et la gestion des résistances aux antibiotiquesIn front of the antibiotic pressure, a wide range of resistance mechanisms exist. They represent an increasing public health issue, which does and will have major consequences on human mortality. Current strategies —mostly based on antibiotic consumption reductions— globally fail to contain this persistent issue. Moreover, even though it is undeniable that the extensive antibiotic use during the past decades has been a driver of antibiotic resistance evolution, its impact on the emergence and the propagation of antibiotic resistance is often overestimated compared to other factors. First, selection on antibiotic resistance cannot be restricted to the medical and veterinary uses of antibiotics. Second, the evolution (i.e. the emergence, maintenance and spread) of a trait in populations also relies on other evolutionary forces and ecological processes. Finally, the intertwining of these factors induces an intricate evolution of resistant phenotypes, relying on several scales ranging from genetic determinism to environmental dynamics. The aim of this thesis is therefore, through an eco-evolutionary approach, to improve the understanding of forces and mechanisms shaping directions and movements of antibiotic resistance genes. To do so, this thesis focuses on aminoglycoside resistance by modifying enzymes. The results of this work highlight the importance of ecological and genomic factors in the circulation of resistance genes, and thus conclude that integrative studies of resistance are thus required. To begin with, this thesis reveals that the distribution of aminoglycoside resistance is loosely linked to variation in aminoglycoside consumption across Europe, but strongly structured by globalization (trade, migration) and even more by ecological connectivity. Subsequent analysis underscores the underestimated role of non-pathogenic bacteria in the horizontal transfer of antibiotic resistance genes at large phylogenetic scales. In the light of these results, this thesis opens up a course of reflection on the study and management of antibiotic resistance
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Subedi, Yagya P. "Cost-Effective Synthesis, Bioactivity and Cellular Uptake Study of Aminoglycosides with Antimicrobial and Connexin Hemichannel Inhibitory Activity". DigitalCommons@USU, 2019. https://digitalcommons.usu.edu/etd/7699.
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Amphiphilic kanamycin is one of the promising class of compounds for the treatment of fungal infections in plants and animal. Factor that lead to the restricting of compounds for commercialization includes, the higher cost of production and poor stability of the compound. However, the new lead, identified from the synthesis and biological testing, can be synthesized on a large scale with a cost comparable to commercial antifungals. The newly reported lead is stable at the acidic and basic conditions. Additionally, this compound has an excellent activity towards Candida auris, a multidrug-resistant superbug.
Heart disease is the leading cause of death in the United States most of which are caused by cardiac ischemia and arrhythmias. Abnormal opening of Cx43 hemichannel can damage the heart muscles and lead to these conditions. A compound which can selectively inhibit the opening of Cx43 hemichannel may pave the way to reducing the mortality rate of heart disease. A selective inhibitor towards Cx43 hemichannel is explored from the synthesis and biological testing of kanamycin derivatives. The synthesis of the new inhibitor is scalable and cost-effective.
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Findlay, Brandon. "Design and synthesis of cationic amphiphiles". American Society for Microbiology, 2010. http://hdl.handle.net/1993/21708.
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Cationic antimicrobial peptides (CAMPs) are produced by plants, animals and bacteria to protect their host against antagonistic microbes. The antitheses of selective antibiotics, these peptides are drawn by electrostatic and hydrophobic interactions to targets as diverse as the bacterial membrane, nucleic acids and serum proteins. This lack of specificity is their greatest strength, as mutations to single genes rarely lead to bacterial resistance. Resistance may be conferred by large scale alterations in cell envelope composition, which generally reduces bacterial fitness in the absence of peptide.
Clinical applications of natural CAMPs are limited, as the peptides are toxic to mammalian cells and rapidly inactivated in vivo by serum albumin and proteases. Faced with these challenges we have prepared a number of CAMP analogues, with the goal of creating lead compounds for further development of antibacterial therapeutics. Much of our work has focused on ultrashort lipopeptides and lipopeptoids, which have properties similar to natural CAMPs and extremely abbreviated sequences. The simple structure of these scaffolds allows rapid creation of CAMP analogues in a brief period of time, allowing us to rapidly explore the structural requirements for CAMP activity. The balance of this work focuses on imparting CAMP-like behaviour to known antibiotics, in order to expand their spectrum of susceptible bacteria and combat the development of drug-resistant bacteria. In particular, the aminoglycosides neomycin and tobramycin have been fused to phenolic disinfectants such as triclosan and biclotymol, in order to improve their diffusion across the bacterial envelope and activity against Gram-negative bacteria.
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Gremyachinskiy, Dmitriy. "Total synthesis of aminomethyl c-glycosides : a thesis". Scholarly Commons, 2001. https://scholarlycommons.pacific.edu/uop_etds/544.
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Bender, Eduardo André. "Caracterização fenotípica e genotípica de amostras de enterococcus spp. isoladas em dois hospitais de Porto Alegre". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/12599.
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As características fenotípicas e genotípicas de 203 isolados de Enterococcus spp. proveniente de diferentes amostras clínicas em dois hospitais localizados na cidade de Porto Alegre, Rio Grande do Sul, Brasil, foram estudadas. As espécies foram identificadas através de testes bioquímicos convencionais e pelo uso do sistema automatizado VITEK 2 (BioMérieux). As concentrações inibitórias mínimas (CIM) para aminoglicosídeos foram determinadas pelo método de diluição em ágar. O alto nível de resistência aos aminoglicosídeos (HLAR) e à ampicilina foi avaliado pelo mesmo método e adicionalmente pelo método de disco-difusão. A diversidade genética de amostras de Enterococcus faecalis com HLAR foi determinada através da digestão do DNA cromossômico com a enzima SmaI seguida de eletroforese em campo pulsado (PFGE). O E. faecalis foi a espécie mais prevalente (93,6%) seguido por E. faecium (4,4%). A resistência entre os isolados clínicos foi de 2,5% à ampicilina, 0,5% à vancomicina, 0,5% à teicoplanina, 33% ao cloranfenicol, 2% à nitrofurantoína, 62,1% à eritromicina, 64,5% à tetraciclina, 24,6% à rifampicina, 30% ao ciprofloxacino e 87,2% à quinupristina-dalfopristina. A prevalência de HLAR foi de 10,3%, sendo 23,6% para gentamicina e 37,4% para estreptomicina. A maioria das amostras sensíveis aos aminoglicosídeos pelo método de disco-difusão apresentaram CIM inferior a 125 μg/mL e 500μg/mL para gentamicina e estreptomicina, respectivamente. A prevalência de Enterococcus resistentes à vancomicina (ERV) foi muito baixa neste estudo. Um grupo clonal predominante foi encontrado entre amostras de E. faecalis com HLR-Ge/St. Os isolados incluídos no grupo clonal foram provenientes de ambos os hospitais, indicando uma disseminação intra e inter-hospitalar deste clone.The phenotypic and genotypic characteristics of 203 Enterococcus spp isolates recovered from different clinical sources of two hospitals in Porto Alegre, Rio Grande do Sul, Brazil, were studied. The species were identified by conventional biochemical tests and the automated system VITEK 2 (BioMérieux). The minimal inhibitory concentrations (MIC) for aminoglycosides were evaluated by agar dilution method. The evaluation of high-level resistance to aminoglycosides (HLAR) and resistance to ampicillin were carried out by the same method as well as by the disc-diffusion method. The genetic diversity of HLAR E. faecalis was assessed by pulsed-field gel electrophoresis of cromossomal DNA after SmaI digestion. The E. faecalis was the most frequent specie (93.6%), followed by E. faecium (4.4%). The percentage of resistance among the clinical isolates was: 2.5% to ampicillin, 0.5% to vancomycin, 0.5% teicoplanin, 33% to chloramphenicol, 2% to nitrofurantoin, 66.1% to erythromycin, 66.5% to tetracycline, 24.6% to rifampicin, 30% to ciprofloxacin and 87.2% to quinupristin-dalfopristin. A total of 10.3% proved to be HLAR, with 23.6% resistant to gentamicin and 37.4% to streptomycin. Most of the aminoglycosides susceptible isolates by the disc-diffusion method presented MIC lower than 125 μg/mL and 500μg/mL for gentamicin e streptomycin, respectively. The prevalence of vancomycin resistance Enterococcus (VRE) was very low in this study. One predominant clonal group was found among E. faecalis exhibiting HLR-Ge/St. The isolates included in the clonal group were recovered from both hospitals, indicating both intrahospital and interhospital spread of this clone.