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Santiago, Marina Joy. "New Genomics Tools and Strategies for Studying Antibiotics and Antibiotic-Resistance in Staphylococcus Aureus." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493460.
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Staphylococcus aureus is a gram positive coccoid pathogen that causes intractable infections in hospitals and communities around the world, and tens of thousands of people die of these infections every year. In order to combat these antibiotic-resistant infections, we need to better understand the genes involved in resistance to the cell stress caused by antibiotic treatment, which will enable the discovery of new antimicrobials and the development of novel therapeutic strategies. We chose to use an approach to this problem that utilizes a new phage-based high frequency of transposition system. In this work, we adapted this system so that transposon mutant libraries can be made and sequenced using next-generation sequencing (NGS) in any strain of S. aureus. We validated our new platform by performing a temperature screen and identifying mutants that are significantly resistant or sensitive to temperature-stress. Next, we created transposon libraries in two MRSA strains to show that this system can be broadly applied to other S. aureus strains, and we used one of these libraries to identify a new interaction between two genes involved in the secretion of sortase-anchored surface proteins. To better understand antibiotic-resistance, we performed Tn-Seq on transposon libraries treated with a small panel of six different antibiotics to identify intrinsic resistance factors to these antibiotics. We identified two new intrinsic resistance factors, SAOUHSC_01025 and SAOUHSC_01050, that sensitize to many cell envelope targeting antibiotics and may be involved in hemolysin regulation. Finally, we expanded this approach to sequence transposon libraries treated with 25 different antibiotics. Based on these data, we were able to develop methods for predicting the mechanism of action of new antibiotics. These methods involve identifying genes upregulated by transposon insertion and applying machine learning algorithms to identify similarities to a curated panel of well-studied antibiotics with known mechanisms of action. This work will enable many new functional genomics studies in S. aureus, and it will allow us to gain a better understanding of antibiotic resistance in this dangerous pathogen.Chemical Biology
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Zhang, Ziyang. "A Platform for the Discovery of New Macrolide Antibiotics." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493421.
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The macrolide class of antibiotics has been widely used to treat bacterial infections for over 65 years. To date, all practical routes to clinically used macrolide antibiotics have relied on the chemical modification of the fermentation product erythromycin, a process referred to as semisynthesis. As bacterial resistance to semisynthetic macrolides emerges, a new approach to the discovery of structurally novel antibiotic candidates is urgently required.
This dissertation presents a general and practical strategy for the synthesis of macrolide antibiotics based on the convergent assembly of simple building blocks. Implementation of this strategy has led to the synthesis of novel macrolide antibiotic candidates in as few as 10 longest linear steps (from building blocks). The synthesis features a thermal macrocyclization reaction that proves generally successful for the construction of several macrolide scaffolds. In the past four years, my coworkers and I have prepared more than 350 fully synthetic macrolides with substantial structural diversity by adaptation of the synthetic route, variation of the building blocks, or a synergic combination of both. Preliminary antimicrobial testing against a panel of Gram-positive and Gram-negative strains reveals that many of the fully synthetic macrolides exhibit promising activities, and several of them are efficacious against pathogens resistant to currently used macrolide antibiotics.
Also described in this dissertation are chemical methods developed specifically for the practical synthesis of two key building blocks. The 3-amino sugar desosamine, a common constituent of many macrolide antibiotics, is synthesized in four steps from methyl vinyl ketone. The key step of the synthesis involves a new method developed for the single-step construction of 3-nitro sugars by the coupling of γ-nitro alcohols and glyoxal. This method has been applied to the preparation of an array of 3-amino sugars analogous to desosamine, which have been incorporated to provide novel macrolides with modified glycosidic residues. The synthesis of silyl enol ether 72 is enabled by an efficient directed Claisen reaction. The reaction of the lithium enolate of a tert-butyl ester and a phenyl ester in the presence of lithium hexamethyldisilazide affords a tert-butyl β-keto ester in high yield. Two subsequent steps transform this product to silyl enol ether 72.Chemistry and Chemical Biology
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Knight, J. "New synthetic methods for the synthesis of #BETA#-lactam antibiotics." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373921.
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Dawson, Janet Ruth. "The synthesis and electrochemical studies of a new valinomycin analogue containing remote functionality." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315981.
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Bower, S. "New methods in acyclic stereocontrol directed towards the synthesis of bafilomycin A1." Thesis, University of Cambridge, 1994. https://www.repository.cam.ac.uk/handle/1810/272787.
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Bouloc, Nathalie Sylvie. "New methodologies for the construction of polyether libraries." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324807.
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Northern, William I. "DISCOVERY OF NEW ANTIMICROBIAL AGENTS USING COMBINATORIAL CHEMISTRY." Wright State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=wright1197323543.
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Mehanni, Magda Mohamed. "Targeting Bacillus subtilis essential genes for the development of new antibiotics." Thesis, University of Sheffield, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419577.
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Murray, Clare Louise. "A new approach to the synthesis of DNA-interactive pyrrolo-[1,4]-benzodiazepin-5-ones." Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321143.
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Templey, Margaret Patricia. "The synthesis of some new heterocyclic analogues of the beta-lactam antibiotics." Thesis, University of Bath, 1988. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384557.
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David, Wendi Marjene. "Studies of a new class of aza-enediynes : aza-Bergman cyclization and the potential use of aza-enediynes as antitumor agents /." Full text (PDF) from UMI/Dissertation Abstracts International, 2000. http://wwwlib.umi.com/cr/utexas/fullcit?p3004248.
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Yoshioka, Alan Yorke. "Streptomycin, 1946 : British central administration of supplies of a new drug of American origin with special reference to clinical trials in tuberculosis." Thesis, Imperial College London, 1998. http://hdl.handle.net/10044/1/8075.
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Louw, Marissa. "New platinum and palladium complexes: their anticancer application." Thesis, Nelson Mandela Metropolitan University, 2010. http://hdl.handle.net/10948/d1016218.
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Novel non-leaving groups were employed in this dissertation to synthesize platinum complexes which can assist in the understanding or improvement of anticancer action. Emphasis was placed on (NS)-chelate and (NN)-chelate platinum complexes. Bidentate (NS)-donor ligands were used as non-leaving ligands in the synthesis of platinum(II) complexes with iodo, chloro, bromo and oxalato groups as leaving groups. These complexes were synthesized and studied since many questions regarding the interaction of sulfur-donors and platinum still exist. These relate to thermodynamic and kinetic factors and their influence on anticancer action. In this dissertation the properties of novel platinum(II) complexes of a bidentate ligand having an aromatic nitrogen-donor atom in combination with a thioethereal sulfur atom capable of forming a five-membered ring with platinum(II) were studied. The general structure of the (NS)-ligands used was 2-((alkylthio)methyl)pyridine. Alkyl groups used were methyl, ethyl, propyl, benzyl and phenyl. Amine complexes of platinum have been studied extensively in the past. However, attention was given to novel aspects of substituted pyridine and imidazole ligands and their corresponding complexes. Amongst these are 2-(2-methylaminoethyl)pyridine, 1-methyl-2-methylaminoethylimidazole and 1-methyl-2-methylaminobenzylimidazole. The leaving groups included chloro, bromo and oxalato. Mononitroplatinum(IV) complexes were prepared using novel synthetic methods. Selected platinum(II) amine complexes were used as starting materials for this synthesis. Some of these compounds exhibit promising anticancer behaviour. (Trans-(R,R)-1,2-diaminocyclohexane)(oxalato)(mononitrochloro)platinum(IV) is a particularly good anticancer agent and has been patented internationally. All these complexes were characterized using mass spectrometry, chromatography, thermogravimetric analysis, kinetic aspects such as ligand exchange rates and finally their anticancer action against three different cancer cell lines was evaluated via cytotoxicity assays. Some of the compounds exhibited particularly good anticancer potential.
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Reinhardt, André [Verfasser], Ines [Gutachter] Neundorf, and Karin [Gutachter] Schnetz. "Antimicrobial peptides as new potential antibiotics / André Reinhardt ; Gutachter: Ines Neundorf, Karin Schnetz." Köln : Universitäts- und Stadtbibliothek Köln, 2017. http://d-nb.info/1137322225/34.
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Zaet, Abdurraouf. "An alternative to conventional antibiotics : a new antimicrobial peptide derived from chromogranin A." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAE004/document.
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Les peptides antimicrobiens (PAMs) représentent des composants importants de l`immunité innée. Ils sont présents dans la plupart des organismes multicellulaires et constituent la première ligne de défense contre les infections. Ils possèdent un large éventail d`activités, une non-toxicité contre les cellules de l`hôte et des effets synergiques avec les antibiotiques conventionnels. Par conséquent, ils peuvent être d`excellents candidats dans le développement de nouveaux antibiotiques pour lutter contre la résistance de microorganismes. Concernant les PAMs dérivés de la chromogranine A (CgA), la cateslytine (Ctl) présente des activités antimicrobiennes directes et des propriétés immunomodulatrices. Dans ma thèse, j`ai cherché à caractériser l`épipeptide D-Ctl, où tous les résidus en conformation-L ont été remplacés par des résidus en conformation-D. Tout d`abord, la stabilité dans les surnageants bactériens et des dosages de l`activité antimicrobienne ont été réalisés, ainsi que l`analyse de viabilité des cellules et des dosages des cytokines libérées par les cellules immunitaires. L`efficacité de D-Ctl a été comparée à celle de L-Ctl contre des souches bactériennes, puis les CMIs ont été déterminées et comparées dans le cas de combinaisons avec des antibiotiques conventionnels, afin de montrer un effet synergique et/ou additif. De plus, D-Ctl ne déclenche pas de résistance chez E. coli. Des tests de cytotoxicité ont été effectués sur plusieurs types de lignées cellulaires et de PBMCs. Les effets inflammatoires aussi ont été testés. Ensuite, le modèle bactérien E. coli MDR a été utilisé pour des analyses physico-chimiques, telles que la microscopie à épifluorescence, la spectroscopie ATR-FTIR et la microscopie à force atomique. Enfin, le brevet D-Ctl a été déposé en 2016 sous le numéro EP 16306539.4 « Nouveau peptide de cateslytine en conformation D ». En conclusion, D-Ctl est capable de tuer rapidement un large spectre de micro-organismes, et il pourrait potentialiser l`effet antimicrobien de plusieurs antibiotiquesAntimicrobial peptides (AMPs) represent important components of innate immunity. They are present in most multicellular organisms and constitute the first line of defense against infections. They exhibit a large spectrum of activities, a non-toxicity against host cells and synergistic effects with conventional antibiotics. Therefore, they can be as excellent candidates in the development of new antibiotics to fight pathogens resistance. Concerning to AMPs derived from chromogranin A (CgA), Cateslytin (Ctl) represents a new antibiotic, which displays direct antimicrobial activities and immunomodulatory properties. In my thesis, I aimed to characterize the epipeptide D-Ctl, where all (L-conformation) residues were replaced by (D-conformation) residues. Firstly, antimicrobial assays were performed, cells viability, immune assays, and the stability in bacterial supernatant was tested. The efficiency of D-Ctl was compared with L-Ctl against bacterial strains, then MICs were determined and compared with combinations in presence of classical antibiotics in order to show synergistic or/and additive effect. Moreover, D-Ctl does not trigger resistance in E. coli. Also, cytotoxicity assays were performed on several types of cell line and PBMCs. Inflammatory effects were tested too. Then, bacterial model E. coli MDR was used for physicochemical analysis such as epifluorescence microscopy, ATR-FTIR spectroscopy and atomic force microscopy. Finally, D-Ctl patent has been deposited in 2016 under the number EP 16306539.4 “New D-configured cateslytin peptide”. To conclude: D-Ctl is able to rapidly kill a broad spectrum of microorganisms, and it could potentiate the antimicrobial effect of several antibiotics
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Lavesa, Curto Manuel. "New strategies for assessing the sequence selective binding of small molecules to DNA." Thesis, University of Southampton, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390604.
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Keshavamurthy, Nishanth, and Venkatesh Akshay Narsipur. "A new approach to purchasing of antibiotics for the Swedish system : A Cost-Benefit Analysis of centralized purchasing." Thesis, Uppsala universitet, Industriell teknik, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-423294.
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The fast-increasing issue of antibiotic unavailability or relatively their shortages in the healthcare system has been the point of concern for many countries. With these shortages come unnecessary costs and the need to utilize less optimal treatment thus increasing the risk of antimicrobial resistance and jeopardizing a patient’s health. This thesis is a collaboration with PLATINEA (Platform for Innovation of Existing Antibiotics), aiming to optimize the usage of antibiotics and to increase the availability of important antibiotics in Sweden. To understand the causes that affect antibiotic unavailability, a good view into the antibiotic and pharmaceutical supply chain is important, especially the purchasing systems of it. The complexities in the purchasing system can lead to interruptions in the antibiotics supply chain thus increasing the risk of antibiotic shortages. These shortages in turn increases the risk of antimicrobial resistance, therefore, the purchasing system requires the need to be analysed extensively. This study aims to explore different purchasing systems and conduct cost-benefit analysis of centralized purchasing system in efforts to help reduce shortages of antibiotics in Sweden. This study is based on the existing literature on centralized and decentralized purchasing and also the pharmaceutical supply chain. Qualitative interviews (semi-structured), multiple reports and articles steered the authors in exploring the purchasing systems and mapping the costs and benefits of centralized purchasing. Throughout the research, emphasis was kept on reducing antibiotic shortages. The findings of this study outline the various costs and benefits of a centralized purchasing system and resulted in the implementation recommendation of it over an existing decentralized purchasing system in Sweden.
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Vila, Farrés Xavier. "Development of new antimicrobial peptides and peptidomimetics and mechanism of resistance to peptide antibiotics." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/285375.
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Nowadays in the world there is a very big problem associated with two factors related to each other. The first factor is the increase in the resistant of certain bacteria, especially the bacteria from the ESKPAE group. The second factor is the dramatically decrease of new antibiotics approved by the FDA. These two problems show that there is an urgent need to find new antibiotics active against these resistant bacteria.
In this thesis, we have tackled two different topics closely related in the race to find new antimicrobials. The first topic tackled was the knowledge of the mechanism of resistance of Gram-negative (A. nosocomialis) and Gram-positive (S. mitis) bacteria. The two antibiotics studied were peptides, colistin and daptomicin, these two peptides are resistant to A. nosocomialis and S. mitis, respectively. Both peptides had a similar mechanism of action related to the membrane of bacteria, therefore we are going to focus just in the modifications in the membrane of the strains resistant to the antibiotic peptides. In S. mitis it was observed, using proteomic techniques, that two proteins related with the membrane were observed. These two proteins has some homologue domains to several proteins involved in daptomycin resistant in S. aureus and Enterococci. In A. nosocomialis, the bacteria showed a high tolerance to colistin, and at 8 mg/L an inflexion point is observed. In this inflexion point, the MIC of colistin, against bacteria increase from <0.1 mg/L to 128 mg/L. These bacteria with high resistance to colistin showed no production of LPS due to the fact that mutations and a stop codon in lpxD gene were observed. This gene is involved in the synthetic pathway of the LPS.
Apart from the understanding of the mechanism of action of peptide antibiotics, we have proposed several peptides and peptidomimetics against Acinetobacter species. We have used two different approaches.
The first approach is the normal approach, testing several peptides or peptidomimetics against the desired bacteria. The first peptides tested were commercially available, and we found mastoparan that was active against both colistin-susceptible and colistin-resistant A. baumannii. This peptide was optimized specially in terms of stability in human serum. After several in vivo trials we did not observe any activity of the peptides tested, however we found a very strong bindoing with some proteins present in the human serum. Frog skin secretions peptides were also tested against colistin-susceptible and colistin-resistant Acinetobacter species, the results obtained were really interesting specially in two peptides. The last peptides tested were peptidomimetics. These peptidomimetics act as an antimicrobial peptide, with two different faces, one face with a cation charge and the other very amphipathic. These peptidomimetics are analogues from the original structure of cholic acid, the structure was modified in order to have antibacterial activity that was found in colistin-susceptible and colistin-resistant A. baumannii, K. pneumonia and P. aeruginosa.
The second approach was completely different, in this case the idea was to block the virulence of bacteria caused by OmpA. This protein is involved in the adherence between bacteria and host cells, therefore several hexacylcic peptides were synthesized in order to inhibit the action of this protein. The results obtained were satisfactory, obtaining good activity in both in vitro and in vivo.Actualment al mon hi ha un greu problema derivat de dos factors relacionats, el primer factor es el increment de la resistència, especialment del bacteris del grup ESKAPE. El segon factor es la disminució dràstica en el nombre d’antibiòtics aprovats per la FDA. Aquests dos problemes fan que hi hagi una urgència per trobar nous antimicrobians efectius en front d’aquestes soques resistents. En aquesta tesi hem abordat dos temes diferents però que estan relacionats a la hora de trobar nous antibiòtics. El primer tema abordat es el de conèixer a fons els mecanismes de resistència de certs antibiòtics, en aquest cas peptídics, en front diferents tipus de soques tant Gram-positives (S. mitis) com Gram-negatives (A. nosocomialis). Els dos antibiòtics peptídics pels que s’ha estudiat la resistència son daptomicina i colistina, en front de S. mitis i A. nosocomialis respectivament. Ambdós pèptids actuen a nivell de membrana, per tant ens centrarem en veure les modificacions produïdes en els soques resistents. Per part de S. mitis resistent a daptomicina, es pot veure una sobreexpressió de dues proteïnes que tenen dominis homòlegs amb altres proteïnes involucrades en la resistència a daptomicina en altres bacteris. En la resistència a colistina es pot apreciar com les soques resistents d’A. nosocomialis presenten una deficiència del LPS. També hem proposat diferents alternatives com a nous antibiòtics, en aquest cas en front de soques A. baumannii. Dos tipus d’aproximacions van ser utilitzades, la primera, i mes clàssica es la de trobar nous antimicrobians, vàrem trobar mastoparan i va diferents paràmetres van ser optimitzat però sense obtindré bons resultats in vivo. També es van provar diferents pèptids provinents de les secrecions de les granotes, presentant bona activitat en front soques d’Acinetobacter, i per últim, les ceragenines, anàlegs del àcid cólic, que tenen bona activitat en front de totes les soques tant colistina sensibles com colistina resistents en Gram-negatius. La segona aproximació es buscant pèptids capaços d’inhibir l’adherència entre el bacteri i la cèl•lula del hoste bloquejant l’acció de la proteïna OmpA. S’ha trobat un pèptid amb bona activitat fins i tot in vivo.
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Morishima, Manabu. "Sustained release of vancomycin from a new biodegradable glue to prevent methicillin-resistant Staphylococcus aureus graft infection." Kyoto University, 2013. http://hdl.handle.net/2433/180460.
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Manabu Morishima, Akira Marui, Shigeki Yanagi, Takamasa Nomura, Naoki Nakajima, Suong-Hyu Hyon, Tadashi Ikeda, and Ryuzo Sakata. Sustained release of vancomycin from a new biodegradable glue to prevent methicillin-resistant Staphylococcus aureus graft infection. Interact CardioVasc Thorac Surg (2010) 11(1): 52-55 doi:10.1510/icvts.2010.232447Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第17856号
医博第3825号
新制||医||1000(附属図書館)
30676
京都大学大学院医学研究科医学専攻
(主査)教授 一山 智, 教授 伊達 洋至, 教授 鈴木 茂彦
学位規則第4条第1項該当
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Jones, Marlon D. "CHIRAL 1, 2-DIAMINO GUESTS IN CHAIN REPLACEMENT PEPTIDOMIMETICS: A NEW HELICAL MOTIF." UKnowledge, 2007. http://uknowledge.uky.edu/gradschool_diss/487.
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Peptides are short, sequence and length specific oligomers composed of small amino acid residues. Nature has refined these peptide sequences and their endogenous function through evolution. In addition, peptides have played an important role in medicine, which has lead to further research into developing peptides as lead pharmaceuticals (therapeutic peptides). Unfortunately, therapeutic peptides are inferior as drug candidates due to their low oral bioavailability; immunogenicity and potential to be attacked by peptidases. Fortunately, peptides can be modified by steric constraints, cyclization, and/or replacement of the peptide backbone itself creating a mimic (peptidomimetic) of the original peptide. Peptidomimetics are deliberately designed to have increased protease resistance, reduced immunogenicity and improved bioavailability when compared to the original endogenous peptide. One such peptide, Magainin is a O One such peptide, Magainin is a well-studied, a-helical peptide found in African clawed frogs. This peptide has antibiotic properties (against pathogenic bacteria), which partly arises from the hydrophilic portion of the peptide having basic amino acid side chains periodically disposed on one side of the a-helix. This property of magainin causes its attraction to negatively charged bacteria cell membranes. Unfortunately, as in the case of other antibiotics, pathogenic bacteria have developed effective countermeasures against magainin. We designed a peptidomimetic based on magainin and implemented a plan to determine what type of molecules could be assembled for a magainin mimic. We successfully utilized molecular modeling (Monte Carlo conformational search), as well as results from previous experiments to elucidate what type of molecules, as well as how many molecules would be necessary to create a novel helical-like magainin peptidomimetic. It was discovered that C2 symmetric diamines would be best at generating the helical-like motif and the amino acid lysine to generate the basic side chain. The next step was the successful connection of two C2 symmetric molecules via a urea linkage and then one more connection to a lysine (a-amino group) residue, creating a short sequence of oligoureas (trimers). Finally, attempts to connect the oligoureas trimers were attempted using a solid-phase synthesis approach to generate a functional magainin mimic.
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Chee, Xavier. "Rational development of new inhibitors of lipoteichoic acid synthase." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269766.
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Staphyloccocus aureus is an opportunisitic pathogen that causes soft skin and tissue infections (SSTI) such as endocarditis, osteomyelitis and meningitis. In recent years, the re-emergence of antibiotic-resistant S. aureus such as MRSA presents a formidable challenge for infection management worldwide. Amidst this global epidemic of antimicrobial resistance, several research efforts have turned their focus towards exploiting the cell-wall biosynthesis pathway for novel anti-bacterial targets. Recently, the lipoteichoic acid (LTA) biosynthesis pathway has emerged as a potential anti-bacterial target. LTA is an anionic polymer found on the cell envelope of Gram-positive bacteria. It comprises of repeating units of glycerol-phosphate (GroP) and is important for bacterial cell physiology and virulence. For example, it is critically involved in regulating ion homeostasis, cell division, host colonization and immune system invasion. Several reports showed that bacteria lacking LTA are unable to grow. At the same time, they suffer from severe cell division defects and also exhibit aberrant cell morphologies. The key protein involved in the LTA biosynthesis pathway is the Lipoteichoic acid synthase (LtaS). LtaS is located on the cell membrane of Gram-positive bacteria and can be divided into two parts: a transmembrane domain and an extra-cellular domain responsible for its enzymatic activity (annotated eLtaS). Given that LtaS is important for bacterial survival and there are no known eLtaS homologues in eukaryotic cells, this protein is an attractive antibacterial target. In 2013, a small molecule eLtaS inhibitor (termed 1771) was discovered. Although 1771 was able to deplete LTA production, the binding mechanism of 1771 to eLtaS remains unknown. Additionally, 1771 could only prolong the survival of infected mice temporarily because of its in vivo instability. Therefore, the need for finding more potent and metabolically stable inhibitors of eLtaS still remains. Computational-aided drug design (CADD) is a cost-effective and useful approach that has been widely integrated into the drug discovery process. The protein eLtaS lends itself to be a good target for CADD since its crystal structure and a known inhibitor (with limited structure-activity data) is available. In this work, I have targeted eLtaS using CADD methodology followed by prospective validation using various biophysical, biochemical and microbiological assays. My project can broadly be sub-divided into three phases: (a) identification of small molecule binding “hot spots”, (b) optimization of existing inhibitor and (c) discovery of new hits. Through a systematic use of different computational approaches, I modelled a plausible 1771-bound eLtaS complex and used the structural insights to generate new inhibitors against eLtaS. To this end, I discovered EN-19, which is a more potent inhibitor of eLtaS. Additionally, by targeting transient cryptic pockets predicted by Molecular Dynamic simulations, I have discovered a new inhibitor chemotype that seems to exhibit a different mode of action against eLtaS. Taken together, my work presents a computational platform for future drug design against eLtaS and reinforces the notion that targeting eLtaS is a viable strategy to combat Gram-positive infections.
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Hagman, Ragnvi. "New aspects of canine pyometra : studies on epidemiology and pathogenesis /." Uppsala : Dept. of Small Animal Clinical Sciences, Swedish Univ. of Agricultural Sciences, 2004. http://epsilon.slu.se/v182.pdf.
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Köhnke, Alessa [Verfasser], and Reinhard [Akademischer Betreuer] Friedrich. "Structural studies of PaFabA- potential target for new antibiotics against Pseudomonas aueruginosa / Alessa Köhnke. Betreuer: Reinhard Friedrich." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2015. http://d-nb.info/1075858666/34.
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Xu, Ling. "Structural studies on S. aureus YlaN and YmfM : exploring unknown biology in the search for new antibiotics." Thesis, University of Sheffield, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444959.
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Starosta, Agata Lucyna [Verfasser], and Roland [Akademischer Betreuer] Beckmann. "Antibiotics and translation : overcoming emerging bacterial resistance to old and new antimicrobials / Agata Lucyna Starosta. Betreuer: Roland Beckmann." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1051777267/34.
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Bułyszko, Ilona [Verfasser]. "Studies on ansamycin antibiotics : mutasynthetic approach towards new rifamycin derivatives and total synthesis of progeldanamycin derivatives / Ilona Bułyszko." Hannover : Technische Informationsbibliothek (TIB), 2016. http://d-nb.info/1126666726/34.
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Li, Linsen. "Development of New Novel Bacterial Topoisomerase Inhibitors as Promising Antibiotics with a 5-Amino-1,3-dioxane Linker Moiety." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu156336340053257.
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Zarins-Tutt, Joseph Scott. "Gene mining of biosynthesis genes and biosynthetic manipulation of marine bacteria for the production of new antibiotic candidates." Thesis, University of St Andrews, 2015. http://hdl.handle.net/10023/7690.
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Natural product drug discovery has traditionally been the corner stone of medicine having provided cures to many of today's most common diseases. In particular, antibiotics have revolutionised healthcare and extended human lifespan. However, since their introduction into the clinic, resistance to these drugs has arisen. With the number of new antibiotics being discovered in recent years declining, and fewer drugs making it past clinical trials, we have reached the point where antibiotic resistant infections have become common place and a serious threat to health and society. There is now an urgent requirement for the discovery of new antibiotics and in particular those with unexploited mode of action. This thesis details the different areas of natural product drug development from discovery through to analogue generation. In Chapter one, the history of natural products as therapeutics is explored with a particular focus on antibiotics and how resistance arises against these agents. It outlines why the discovery of new antibiotics is so important and new methods used to facilitate this search. Chapter two follows with the development of a screening platform for antibiotic induction, using the model Streptomyces; Streptomyces coleiolor M145. A variety of culture additives are explored for their ability to induce secondary metabolism production. Chapter three then details the sampling and identification of microbes from a pseudo-marine environment and their screening for their ability to produce secondary metabolites with antibiotic properties. The second half of this thesis centres on the non-ribosomal peptide echinomycin. Collaborators Aquapharm supplied the marine derived strain AQP-4895, capable of producing echinomycin. Chapter four details the establishment of AQP-4895 culturing conditions and the shift observed in production profile. Next Chapter five looks at producing echinomycin analogues through precursor directed biosynthesis. A range of halogenated quinoxaline carboxylic acids are synthesised and fed to AQP-4895, and the respective echinomycin analogues monitored by LC-MS. Chapter Six then aims to direct biosynthesis of the halogenated analogues, using mutasynthesis. Due to the lack of genetic data available surrounding the strain, an unusual approach was taken, using iPCR to create a template for homologous recombination.
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Breydo, Leonid P. "New mechanisms of DNA damage and non-covalent DNA binding by the antitumor antibiotic Leinamycin." free to MU campus, to others for purchase free online, 2002. http://wwwlib.umi.com/cr/mo/preview?3052153.
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Viegelmann, Christina Victoria. "Metabolomics as a tool in the identification and production of new marine-derived antibiotics from sponges and endosymbiotic bacteria." Thesis, University of Strathclyde, 2014. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=24876.
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Metabolomic methods can be utilised to screen diverse biological systems for potentially novel and sustainable sources of antibiotics and pharmacologically-active drugs. Marine sponges and their endosymbionts have proven to be abundant sources of bioactive compounds. HR-LCFTMS and NMR were used in the identification of compounds isolated from a marine bacterium and its host sponge, as well as in the dereplication and metabolic profiling of other sponge-associated bacteria.24-Methylenecholesterol and two novel steroids, 24-vinyl-cholest-9-ene-3β,24-diol and 20-methyl-pregn-6-en-3β-ol, 5α,8α-epidioxy, all significantly active against Trypanosoma brucei and moderately active against Mycobacterium marinum were isolated from the Irish Sea sponge Haliclona simulans. Extracts from SM8, the Streptomyces sp. isolated from H. simulans demonstrated antibacterial and antifungal activities. NMR spectroscopy identified the major components of the antibacterial fractions as polyhydroxylated saturated fatty acids. HR-LCFTMS assisted in identifying members of the antimycin A family in the antifungal fractions. This was further confirmed using gene knockout studies. Three butenolides were also isolated from the SM8 extracts. HR-LCFTMS was applied to the dereplication of extracts from bacteria from marine sponges. EG4, a Microbacterium sp. isolated from Callyspongia aff. implexa, was selected and its cultivation optimised from small scale to larger scale production, under different media conditions, with the aid of metabolomic methods and multivariate analysis to identify and trace biomarkers. In addition, several compounds that were active against T. brucei and M. marinum and Nocardia farcinica were isolated and identified. Metabolomics has become a powerful tool in systems biology which allows us to gain insights into the potential of natural marine isolates for synthesis of significant quantities of promising new agents, and allows us to manipulate the environment within fermentation systems in a rational manner to select the desired bioactive metabolome.
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Rodriguez, Roman. "New method for determination of â-lactam antibiotics by means of Diffuse Reflectance Spectroscopy using polyurethane foam as sorbent." Gerhard-Mercator-Universitaet Duisburg, 2006. http://www.ub.uni-duisburg.de/ETD-db/theses/available/duett-01052006-142652/.
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The present study was focused to develop an analytical method to analyse â-lactam antibiotics present in aqueous solutions and able to be applied directly in the fields. The method here presented is based on the chemical reaction between â-lactam antibiotics with phosphomolybdic acid, a heteropolyacid able to be reduced by the thiols obtained after the acid hydrolysis of the â-lactam antibiotics. The blue product obtained, which is proportional to the antibiotic amount, is adsorbed on polyurethane foam, and the intensity of color is directly evaluated on the solid material by means of diffuse reflectance spectroscopy. For all six evaluated â-lactam antibiotics (amoxicillin, ampicillin, penicillin V, penicillin G, cefotaxime, cefuroxime), the analytical parameters achieved were: LOD = 0.03 µg/ml, LOQ = 0.1 µg/ml, RSD = 4.0 %. The study of possible interferences showed that using solid phase extraction is possible to eliminate even strong interferences as ascorbic acid, cysteine and reducing salts like stannous chloride. The present method has avoided, as much as possible, the use of expensive and contaminating solvents and chemical reagents. The method presents the possibility to be applied using only a desktop scanner and a personal PC for measuring the color of the adsorbed material on the PUF.
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Hörtner, Simone Rachel. "Towards a new class of antibiotics for the treatment of Shigellosis : design and synthesis of inhibitors of tRNA-guanine transglycosylase /." Zürich : ETH, 2007. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17158.
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Coquin, Laurence. "Synthesis and biological activity of heterocycles and heptapeptide derivatives related to microcin B17 : potential leads for new herbicides and antibiotics." Thesis, University of East Anglia, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426422.
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CIARAMELLI, CARLOTTA. "Synthesis and characterization of new small-molecule ligands of LPS binding proteins." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2015. http://hdl.handle.net/10281/77016.
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Lo scopo del presente lavoro è la progettazione, la sintesi e la caratterizzazione di nuove small molecules, attive come ligandi di LPS (lipopolisaccaridi)-binding proteins. Gli LPS, o endotossine batteriche, sono macromolecole anfifiliche ubiquitarie sulla membrana esterna dei batteri Gram-negativi. Le proteine che legano gli LPS studiate nel corso di questo progetto di tesi di dottorato appartengono a due categorie: le proteine batteriche di trasporto Lpt e il sistema recettoriale TLR4, che comprende anche i co-recettori LBP, CD14, MD2.
Le proteine Lpt, e in particolare la proteina LptC, sono responsabili del meccanismo di esportazione del LPS alla superficie cellulare, che è uno step fondamentale della via biosintetica dell’LPS. Pertanto, la biogenesi dell’LPS rappresenta un target ideale per lo sviluppo di nuovi antibiotici contro i batteri Gram-negativi. Inoltre, le strutture delle proteine Lpt sono state risolte, ma il meccanismo di trasporto è ancora da elucidare.
Nel presente lavoro di tesi sono stati utilizzate diverse tecniche per studiare l'interazione tra LPS e LptC, con particolare attenzione agli studi di interazione via NMR. Inoltre, un nuovo LPS fluorescente è stato prodotto ed è stato utilizzato come tool per studi di interazione LPS-LptC con tecniche di fluorescenza. Sono state anche sviluppate alcune nuove molecole sintetiche. Questi glicolipidi sono stati progettati e sintetizzati per ottenere ligandi di LptC e, in prospettiva, potenziali antibiotici contro i batteri Gram-negativi.
Il Toll-like receptor 4 (TLR4), il recettore dell'immunità innata, riconosce l’LPS aiutato da altre proteine (LBP, CD14 e MD-2) ed è responsabile dell'induzione della risposta infiammatoria. Molecole sintetiche in grado di modulare l'attività dei recettori dell’immunità innata sono un potente mezzo per studiare il sistema recettoriale TLR4 e hanno grande interesse farmacologico come adiuvanti vaccinali (agonisti), agenti antisepsi e anti-infiammatori (antagonisti).
L’attività biologica di glicolipidi con una funzione amminica (IAXO-102) come antagonisti del TLR4 è stata chiaramente dimostrata dal nostro gruppo di ricerca. La sintesi di molecole derivate da IAXO-102, che mantengano l'attività biologica del precursore, è stato un obiettivo di questo lavoro. In particolare, sono state portate a termine le sintesi di sonde fluorescenti, utilizzate per studi di interazione, derivati zwitterionici e molecole dimeriche. Nei nostri laboratori sono stati ottenuti anche antagonisti anionici del TLR4 con una struttura chimica più simile a Lipide A. Lo scopo di questo lavoro è stato valutare, tramite esperimenti NMR, la loro capacità di legare co-recettore dell'immunità innata MD-2.
Il carattere anfifilico degli analoghi sintetici del lipide A sintetizzati finora è spesso associato ad una bassa solubilità in acqua e a scarsa biodisponibilità. Invece, i composti attivi sul TLR4 di origine naturale hanno una migliore solubilità e biodisponibilità. La modifica chimica di queste strutture è molto utile per modulare l'attività biologica e per migliorare la specificità nei confronti del target. Di conseguenza, in una fase successiva di questo lavoro di tesi, è stata intrapresa la sintesi di nuove molecole con strutture chimiche ispirate ai modulatori naturali del TLR4. Recentemente è stato dimostrato che alcuni composti fenolici estratti da olio di oliva hanno una buona attività come antagonisti del TLR4. Pertanto, la sintesi di alcuni analoghi di queste molecole è stata eseguita per ottenere nuovi potenziali antagonisti del TLR4, con una migliore solubilità in acqua e una ridotta tossicità.The purpose of this work is the design, synthesis and characterization of new small molecules, active as ligands of two different lipopolysaccharide (LPS)-binding proteins. LPS, or bacterial endotoxin, is an amphiphilic macromolecule ubiquitous on the outer membrane of Gram-negative bacteria. The LPS binding proteins studied during this thesis project belong to two classes: the bacterial proteins of the Lpt transport machinery and the mammalian TLR4 receptor system, including the co-receptors LBP, CD14, MD-2. Lpt proteins, and in particular the protein LptC, are responsible for the export mechanism of LPS to the cell surface of Gram negative bacteria, which is a fundamental step of the LPS biosynthetic pathway. Therefore, the LPS biogenesis represents an ideal target for development of novel antibiotics against Gram-negative bacteria. Moreover, the structures of Lpt proteins have been elucidated, but very little is known about the mechanism of LPS transport. In this thesis work different techniques were used to study the interaction between LPS and LptC, particularly NMR binding studies. Moreover, a new fluorescent LPS was produced and it was used as a tool to perform LPS-LptC interaction studies with fluorescence techniques. Some new synthetic molecules were also developed during this thesis. Glycolipidic small molecules were designed and synthesized in order to obtain LptC ligands and, in perspective, potential antibiotics against Gram-negative bacteria. Toll-like receptor 4 (TLR4), the innate immunity receptor, recognizes LPS, helped by other proteins (LBP, CD14 and MD-2), and it is responsible for the induction of inflammatory responses. Synthetic small molecules able to modulate innate immunity receptors activity are a powerful mean to study the TLR4 receptor system and have great pharmacological interest as vaccine adjuvants (agonists), antisepsis and anti-inflammatory agents (antagonists). Antagonist activity on TLR4 receptor system of amino glycolipids (IAXO-102) was clearly demonstrated by our research group. The synthesis of molecules derived from IAXO-102 which retain the biological activity of the precursor was a target of this work. In particular, the synthesis of fluorescent probes, used for binding studies, zwitterionic derivatives and dimeric molecules were performed. Anionic TLR4 antagonists with a chemical structure more similar to Lipid A were also obtained in our labs. The aim of this work was the evaluation via NMR binding experiments of their ability to bind the innate immunity co-receptor MD-2. The amphiphilic character of the synthetic lipid A analogues synthesized so far is often associated with low water solubility and poor bioavailability. In this respect, the natural TLR4-active compounds have better solubility and bioavailability. The chemical modification of these structures is very helpful to modulate their biological activity and to enhance target specificity. Consequently, in a later stage of this work, the synthesis of new small molecules with chemical structures inspired to natural TLR4 modulators was pursued. Very recently it was found that some phenolic compounds from olive oil extracts presented a good activity as TLR4 antagonists. The synthesis of some analogues of these molecules was performed to obtain new potential TLR4 antagonists with better water solubility and reduced toxicity.
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Jorba, Pedrosa Marta. "Outer membrane: a key obstacle for new antimicrobial agents." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/672746.
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INTRODUCTION: Antimicrobial resistance is one of the world’s major challenges in both microbiology and public health since infections caused by multidrug-resistant bacteria are reaching alarming levels. The world is currently facing a global antibiotics crisis and some new strategies need to be explored to tackle these resistant infections.
The outer membrane is a differential structure of Gram-negative bacteria that works as a highly effective selective permeability barrier. Thus, the permeation through the Gram- negative cell envelope is a challenge for drug compounds to reach their targets.
One path to open new antimicrobial perspectives is the chemical modification of old antimicrobial compounds that may result in optimized drugs with improved antimicrobial properties. In this context, the activity exploration of the derivatives of Microcin J25 and Trimethoprim was carried out.
HYPOTHESIS: The main hypotheses of this thesis are that chemical modifications of current antibiotics may significantly contribute to overcoming the problems arising from the increase and spread of antibiotic resistance in bacteria. Moreover, the combination of these modified compounds with old-rescued antibiotics may contribute to the solution bases of the problem caused by resistance.
Objectives: The main objective of this thesis is to determine the antimicrobial properties of chemically modified drug compounds. The secondary objectives of this thesis are divided in two parts:
Microcin J25: Study of the antimicrobial activity of the modified Microcin J25 as well as determination of its toxicity.
Trimethoprim: Study of the antimicrobial activity and cytotoxicity of the Trimethoprim derivatives, exploration of the effect of the new derivatives on the Dihydrofolate Reductase (DHFR) enzyme and start a computational approach to decipher the intimal mechanisms of action.
METHODOLOGY: The antimicrobial activity of the derived compounds was explored against planktonic bacteria (studying the Minimum Inhibitory Concentration and the FIC index) and against sessile bacteria (exploring the Minimum Biofilm Eradication Concentration and the Biofilm Prevention Concentration). The growth curves of several microorganisms in contact with these compounds and in combination with colistin were also studied. The cytotoxicity of all the compounds was tested. An enzymatic assay with
E. coli DHFR as well as a docking modelling were carried out to investigate the mechanism of action of TMP derivatives.
RESULTS: With respect to Microcin MccJ25, it has been detected that the chemical modification of the compound resulted in a new peptide without antimicrobial activity. It acted synergistically with sublethal concentrations of colistin.
When referring to Trimethoprim (TMP), some of the new derivatives showed antibacterial similar to that of TMP. Moreover, almost all the new TMP-like compounds acted synergistically with SMX. P. aeruginosa PAO1 was fully resistant to TMP and all its derivatives as well as to the combination of TMP-SMX. The combination of TMP, TMP- like molecules and SMX with colistin enhanced their antimicrobial efficacy against E. coli, P. aeruginosa and S. marcescens. Compounds 1a and 1b, like TMP, strongly inhibited the activity of the E. coli DHFR. Additionally, it was detected that the heterocyclic ring of the compound 1a fills the pocket occupied by the nicotinamide ring of NADPH.
CONCLUSIONS: The present PhD thesis has led to some relevant conclusions. With respect to Microcin MccJ25, the chemical modification of the compound avoided its detection by the membrane receptor FhuA. Moreover, it did not affect the interaction with the target and, as the polymyxin facilitated the microcin entrance across the membrane, once inside the cell, the new compound retained its ability to inhibit the growth of bacteria.
When referring to Trimethoprim (TMP), the derivatives showed interesting antimicrobial activities acting synergistically with SMX. The combination of TMP, TMP- like molecules and SMX with colistin enhances their antimicrobial efficacy by permeabilizing the cells. Compounds 1a and 1b, like TMP, strongly inhibited the activity of the E. coli DHFR and it was suggested that both molecules interact with the analogues during inhibition.
The search of new antimicrobial compounds is one of the main pathways to overtake bacterial resistance to antibiotics. All putative compounds should be tested in conditions in which outer membrane role as permeability barrier is inactivated. Their assay together with sublethal concentrations of colistin is proposed as one of the methods of election.INTRODUCCIÓN: La resistencia a los antimicrobianos es uno de los principales desafíos del mundo tanto en microbiología como en salud pública, ya que las infecciones causadas por bacterias multirresistentes están alcanzando niveles alarmantes. Una opción para abrir nuevas perspectivas antimicrobianas es la modificación química de compuestos antimicrobianos ya existentes que pueden resultar medicamentos optimizados con propiedades antimicrobianas mejoradas. En este contexto, en esta tesis se llevó a cabo la exploración de la actividad de los derivados de Microcina J25 y Trimethoprim. HIPÓTESIS: Las principales hipótesis de esta tesis son que las modificaciones químicas de los antibióticos actuales y la combinación de estos compuestos modificados con antibióticos antiguos rescatados pueden contribuir significativamente a superar los problemas que surgen del aumento y la propagación de la resistencia a los antibióticos en las bacterias. Objetivos: El principal objetivo de esta tesis es determinar las propiedades antimicrobianas de compuestos químicamente modificados. Metodología: Se exploró la actividad antimicrobiana de los compuestos derivados frente bacterias planctónicas y frente bacterias sésiles. También se estudiaron las curvas de crecimiento de varios microorganismos en contacto con estos compuestos y en combinación con colistina. Se ensayó la citotoxicidad de todos los compuestos. Se llevó a cabo un ensayo enzimático con E. coli DHFR así como un modelo de docking. RESULTADOS Y CONCLUSIONES: Con respecto a la Microcina MccJ25, se detectó que la modificación química del compuesto dio como resultado un nuevo péptido sin actividad antimicrobiana ya que se evitó su detección por el receptor de membrana FhuA. Esta actuó de forma sinérgica con concentraciones subletales de colistina debido a que la polimixina facilitó la entrada de la microcina a través de la membrana y, una vez dentro de la célula, el nuevo compuesto conservó su capacidad para inhibir el crecimiento de las bacterias. En cuanto a Trimethoprim (TMP), algunos de los nuevos derivados mostraron un efecto antibacteriano similar al de TMP. Además, casi todos los nuevos compuestos actuaron sinérgicamente con SMX. P. aeruginosa PAO1 fue totalmente resistente a TMP y todos sus derivados, así como a la combinación de TMP-SMX. La combinación de TMP, análogos de TMP y SMX con colistina mejoró su eficacia antimicrobiana contra E. coli, P. aeruginosa y S. marcescens ya que ésta permeabilizó las células. Los compuestos 1a y 1b, como TMP, inhibieron la actividad de la DHFR de E. coli. Además, se observó que el anillo heterocíclico del compuesto 1a llena el bolsillo ocupado por el anillo de nicotinamida de NADPH y se sugirió que ambas moléculas interactúan con los análogos durante la inhibición.
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Huang, Qinhua. "New Palladium-Catalyzed Approaches to Heterocycles and Carbocycles." Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2004. http://www.osti.gov/servlets/purl/835382-35f7N8/webviewable/.
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Paulson, Philip Theodor. "California Livestock Owners: An Assessment of Familiarity with New Antimicrobial Rules and Access to Educational Outreach." DigitalCommons@CalPoly, 2019. https://digitalcommons.calpoly.edu/theses/2012.
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The purpose of this research is to support the California Department of Food & Agriculture (CDFA) with education and outreach about recent changes regarding antimicrobial use in livestock, and to enhance their emergency communications network. This was done by characterizing a population of small-scale livestock owners underserved with regards to educational outreach about animal health issues, such as antimicrobial use rules. The project also seeks to enhance public understanding of the importance of responsible antimicrobial use in animal and human health.
To accomplish this, the study used a survey administered in person at local farm supply stores and online to investigate the level of understanding of antimicrobial rules among livestock owners in San Luis Obispo county. The survey gathered information about the livestock owners’ practices, connection to livestock groups, and access to information pertaining to animal health among other things.
The results of the survey showed that respondents were largely unaware of new rules pertaining to use of antimicrobials in livestock. Familiarity with California rules of this kind was used as an indicator of access to information about animal health and was found to correlate positively with knowledge about antimicrobial resistance and familiarity with federal rules concerning antimicrobial use in livestock. As predicted, respondents with a connection to 4-H and FFA had greater familiarity with both federal and state rules concerning antimicrobial use in livestock.
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Leslie, J. Michelle. "N-Thiolated b-lactam antibiotics : synthesis and structure-activity studies of C3 oxygenated derivatives and attachement to new, functionalized caprolactone monomers and polymers." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001685.
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Löfgren, Christina. "Pharmacological and clinical studies of new ways to improve cytostatic treatment of acute myelocytic leukemia : in vitro and in vivo studies /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-183-0/.
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Jowitt, Deborah Mary. "The H-bug epidemic the impact of antibiotic-resistant staphylococcal infection on New Zealand society and health 1955-1963 : a thesis presented in partial fulfillment of the requirements for the degree of Masters of Health Science (Midwifery), Auckland University of Technology, 2004." Full thesis. Abstract, 2004.
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Park, Tansol. "Towards a Better Understanding of the Metabolism, Physiology, and Ecology of Rumen Protozoa: New Insights from Culturomics and Genomics." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1511959620750916.
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Liu, Minhao. "Structural studies of a potent Escherichia coli RNAP inhibitor T7 Gp2 and its interaction with RNAP β' subunit : an early step towards devising new antibiotics." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/9038.
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Infection of Escherichia coli by the T7 bacteriophage leads to the rapid and selective inhibition of the host RNA polymerase (RNAP) - a multisubunit enzyme responsible for gene transcription - by a small (7 kDa) phage-encoded protein called Gp2 (Gene 2 protein). Gp2 is also a potent inhibitor of E. coli RNAP in vitro. Here, we provide the first structural insight into Gp2. The structure of Gp2 revealed a distinct separation of positive and negative surface charges on different sides of the molecule. The two highly exposed arginines are also in agreement with the mutagenesis studies, which suggested that they have an important role on the Gp2-RNAP interaction and Gp2's function. We have also provided the structural insight into a small domain of the RNAP β' subunit, the β' jaw domain, which is known from previous mutagenesis studies to possess the site for Gp2 binding. Evidence for an interaction between Gp2 and β' jaw domain were provided by Nuclear Magnetic Resonances (NMR) titration experiments. The Gp2-Jaw complex structure solved by NMR spectroscopy has largely facilitated the elucidation of Gp2's inhibition mechanism by allowing the construction of a Gp2-RNAP complex model, which also suggested other possible interaction sites between RNAP and Gp2. Furthermore, the new selective methyl labelling methods may provide experimental data for interactions between Gp2 and RNAP by NMR. RNAP has been used as an important target for broad-spectrum antibacterial therapy and for anti-tuberculosis therapy. According to the structural model of the Gp2-RNAP complex, the binding site of Gp2 is distal to the catalytic cleft, which does not overlap with the binding site of the antibiotic Rifamycin. Understanding the inhibition mechanism of Gp2 may thus open up a new route for the development of RNAP targeted antibiotics.
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Adeyemi, Oluwatosin Oluwakemi. "Comparative in-vitro activities of trimethoprimsulfamethoxazole and the new fluoroquinolones against confirmed extended spectrum beta-lactamase producing Stenotrophomonas maltophilia in Nkonkobe Municipality, Eastern Cape environment." Thesis, University of Fort Hare, 2012. http://hdl.handle.net/10353/d1007576.
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Stenotrophomonas maltophilia is increasingly emerging as an opportunistic pathogen of global concern. Due to its inherent resistance to several classes of antibiotics including carbapenems and its ability to acquire mobile resistance elements, treatment of infections caused by S. maltophilia is a constant challenge for clinicians. Trimethoprim-sulphamethoxazole (TMP-SMX) is the generally accepted antibiotic of choice for the treatment of infections caused by this organism, but resistance to the drug is increasingly being reported; hence, the need for alternative therapeutic options. In this study, the antimicrobial susceptibility profile of 110 commensal S. maltophilia isolates obtained from Nkonkobe municipality, Eastern Cape Province, Republic of South Africa was investigated. Twenty-one antibiotics including TMP-SMX and the newer fluoroquinolones; levofloxacin, gatifloxacin and moxifloxacin were included in the antibiotic panel. About 63.4 percent of the isolates were susceptible to TMP-SMX with a resistance rate of 28.2 percent. The fluoroquinolones were more effective with susceptibilities ranging from 76 percent to 94.7 percent. Resistance to the fluoroquinolones ranged from 1.3 percent to 2.7 percent. Levofloxacin was the most effective fluoroquinolone tested. Phenotypic dectection of extended spectrum β-lactamases (ESBLs) showed double disc synergy test (DDST) positivity in 59.5 percent of the isolates. Cefepime was the most sensitive indicator cephalosporin in the DDST with 77.3 percent of suspected ESBL-producing isolates showing cefepime-clavulanic acid synergy. Isolates exhibited nine different ESBL phenotypes, however, PCR amplification of the bla genes revealed four isolates that possessed genes belonging to the CTX-M group (CTX-M-1 and CTX-M-8 groups). ESBL genes are usually carried on mobile elements such as plasmids and transposons which may also bear genes that mediate resistance to aminoglycosides, tetracyclines, TMP-SMX and fluoroquinolones. ESBL positive isolates appeared more susceptible to the fluoroquinolones compared to TMP-SMX but there was no significant relationship between ESBL production and susceptibility to these drugs (p > 0.05). The newer fluoroquinolones are a possible alternative treatment option for S. maltophilia infections in this environment but further studies and clinical investigations are needed to determine the in vivo efficacy of these drugs.
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Meier, Kirstin Anne [Verfasser]. "Identification of new molecular targets and antibiotics as novel strategies against filarial infections : Characterization of lipid II biosynthesis in Wolbachia endobacteria / Kirstin Anne Meier." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/118973060X/34.
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Meier, Kirstin [Verfasser]. "Identification of new molecular targets and antibiotics as novel strategies against filarial infections : Characterization of lipid II biosynthesis in Wolbachia endobacteria / Kirstin Anne Meier." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/118973060X/34.
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Canter, Brandi N. "Modeling Antibiotic Resistance when Adding a New Antibiotic to a Hospital Setting." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/honors/30.
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As of now, not many pharmaceutical companies are producing new categories of antibiotics to fight bacterial infections. Therefore, bacteria are building up a resistance to the medications commonly used. Often, antibiotic resistance begins within a hospital. To combat resistance, researchers completed several studies using cycling of the medications that are already in place, but they found either no improvement or the resistance increased with this type of setting. In addition, although preventative infection control measures have been shown to decrease antibiotic resistance for some antibiotics, the level of antibiotic resistance found in hospitals is still extremely high. This motivates the main goal of this thesis: to quantify how much the overall resistance can be lowered by simply adding one new drug to the regimen.
The process of adding a new antibiotic can be quantified using mathematical models that show the flow of patients colonized with various types of bacteria into, out of, and within the hospital. Deterministic models can be used to model the spread of resistant bacteria in hospitals with a relatively large number of beds. However, not all hospitals are large enough to accurately determine the effects using a deterministic model; thus, we must use stochastic models, where mathematical formulations include probability in ways that describe intrinsic random fluctuations, typical of infection processes at smaller scales.
In examining the addition of a new antibiotic within a hospital, we consider different administration protocols, either assuming that physicians are equally likely to prescribe the new antibiotic as they are to prescribe existing antibiotics or that physicians prescribe the new antibiotic to only a targeted population of patients. We will examine the variation in the expected level of overall resistance in a hospital depending on the administration procedure as well as the whether the hospital is large (deterministic model) or small (stochastic model). We will conclude with initial results for fitting these models to simulated data using common inverse problem methodology.
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Eckert, Tobias. "Efficacy of longterm antibiotic treatment for chronic lyme-borreliosis/post-lyme syndrome : a systematic review /." Bern, 2007. http://www.public-health-edu.ch/new/Abstracts/ET_26.03.08.pdf.
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Bates, Andrew D. "New reactions in tetramic acid synthesis." Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252629.
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Ringan, Neil S. "New reactions of ceph-3-ems." Thesis, University of Abertay Dundee, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.329125.
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Afouda, Pamela. "Microbiote ancien versus microbiote contemporain : analyses culturomics, métagénomique et comparaisons génomiques." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0581.
Full textAbstract:
L’exploration du microbiote humain a connu un tournant ces dernières années avec l’apport significatif de l'approche « microbial culturomics », qui a permis d’augmenter de façon considérable le répertoire de microbes humain cultivables. Mais cette approche n’a jamais été appliquée à l’étude d’écosystèmes anciens. Dans cette thèse, nous avons associé culturomics et métagénomique pour explorer la composition bactérienne d’un échantillon environnemental ancien vieux de 2,7 millions d’années : le permafrost sibérien. Nous avons identifié 28 espèces bactériennes que nous avons séquencées puis comparer à leurs homologues contemporaines en analysant leurs profils de résistances et en étudiant leurs évolutions génomiques principalement par détermination de la composition en SNPs dans les génomes. Les souches du permafrost hébergeaient de 2-51 gènes de résistances appartenant à 20 classes d’antibiotiques différentes et étaient phénotypiquement résistantes à 2-8 classes d’antibiotiques différentes. L’étude génomique montre que la contenance génomique des souches contemporaines et anciennes étaient similaires mettant ainsi en évidence une évolution moléculaire réduite pendant 2,7 millions d’années.Dans un second travail, nous avons évalué l’impact de « la désinfection à l’éthanol » sur la composition du microbiote intestinal pouvant servir de bactériothérapie. L’application de 22 conditions de culture sur 11 selles de donneurs de greffes fécales désinfectées à l’éthanol a identifié 254 espèces bactériennes majoritairement anaérobies. Parmi elles, 242 n’avaient jamais été signalées en essais de bactériothérapie et représentent des candidats potentiels pour des études futuresThe exploration of the human microbiota has been a turning point in recent years with the significant contribution of the « microbial culturomics » a high throughput culture technique that has significantly increased the repertoire of cultivable human microbes. But this approach has never been applied to the study of ancient ecosystems. To start, we have combined culturomics approach with metagenomics to explore the bacterial composition of an ancient environmental sample dated to 2.7 million years old: Siberian permafrost. We identified 28 bacterial species that we have sequenced and then compared to their contemporary counterparts by analyzing their resistance patterns and studying their genomic evolution mainly by determining the single nucleotide polymorphism (SNPs) composition in the genomes. We found that permafrost strains harbored two to fifty-one antibiotic resistance genes belonging to twenty different antibiotic class and were phenotypically resistant to 2-8 different antibiotic class. Genomics studies show that contemporary genomes and ancient strains were quite similar, thus revealing a reduced molecular evolution for 2.7 million years.Secondly, we evaluated the impact of "ethanol disinfection" on the intestinal microbiota's composition that can be used as bacteriotherapy, particularly to treat Clostridium difficile infections. The application of twenty-two culture conditions on 11 stools of faecal graft donors previously disinfected with ethanol allowed the isolation of 254 predominantly anaerobic bacterial species. Among these, 242 had never been reported in bacteriotherapy trials and represent potential candidates for future studies