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Chung, Whasun Oh. "Macrolide resistance and its linkage to tetracycline resistance /". Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/9279.
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Powell, James Patrick. "Antibiotic Diversity and Bacterial Resistance". Available to users online at:, 2007. http://hdl.handle.net/10156/1303.
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Messer, Janet Mariam. "Bacterial resistance ot glycopeptide antibiotics". Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239488.
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Brown, Keith L. "Heat resistance of bacterial spores". Thesis, University of Nottingham, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317036.
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Sütterlin, Susanne. "Aspects of Bacterial Resistance to Silver". Doctoral thesis, Uppsala universitet, Klinisk mikrobiologi och infektionsmedicin, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-247472.
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Bacterial resistance to antibiotics has increased rapidly within recent years, and it has become a serious threat to public health. Infections caused by multi-drug resistant bacteria entail higher morbidity, mortality, and a burden to health care systems. The use of biocides, including silver compounds, may affect the resistance to both biocides and antibiotics and, thereby, can be a driving factor in this development. The aim of the following thesis was to investigate the frequency of silver resistance and the effects of silver exposure on bacterial populations being of clinical significance and from geographically different parts of the world. Furthermore, it explored the genetic background of silver resistance, and if silver could select directly or indirectly for antibiotic resistance. By a range of methods, from culture in broth to whole genome sequencing, bacterial populations from humans, birds and from the environment were characterized. The studies showed that sil genes, encoding silver resistance, occurred at a high frequency. Sil genes were found in 48 % of Enterobacter spp., in 41 % of Klebsiella spp. and in 21 % of all human Escherichia coli isolates with production of certain types of extended-spectrum beta-lactamases (CTX-M-14 and CTX-M-15). In contrast, silver resistance was not found in bird isolates or in bacterial species, such as Pseudomonas aeruginosa and Legionella spp., with wet environments as their natural habitat. One silver-resistant Enterobacter cloacae strain was isolated from a chronic leg ulcer after only three weeks of treatment with silver-based dressings. The in-vivo effects of these dressings were limited, and they failed to eradicate both Gram-positive and Gram-negative bacteria. The activity of silver nitrate in vitro was bacteriostatic on Gram-positive species such as S. aureus and bactericidal on Gram-negative species. In Enterobacteriaceae, sil genes were associated with silver resistance phenotypes in all but one case. Using whole genome sequencing, single nucleotide polymorphisms in the silS gene were discovered after silver exposure in isolates with expressed silver resistance. This resistance could co-select for resistance to beta-lactams, co-trimoxazole and gentamicin. The findings of this thesis indicate that silver exposure may cause phenotypic silver resistance, and it may reduce the susceptibility to mainly beta-lactams and select for bacteria with resistance to clinically important antibiotics.
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Crossland, Richard J. "Mathematical modelling of bacterial mercury resistance". Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/30521/.
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A mathematical model of mercury resistance was designed which describes the following reactions: the cellular uptake and volatilisation of Hg2+, binding of the DNA by the regulator, mer protein synthesis, and dilution of quantities by cell growth. A total of 66 biological experiments were then selected from the scientific literature from studies of Tn21 and Tn501 in E. coli at 37 °C. These experiments were repeated in the computer simulation and the information from their 489 data points was incorporated into the 16 parameters of the model using the Metropolis-Hastings algorithm. This model is very useful biology for four reasons. Firstly, it shows whether the data from existing biological experiments are consistent with each other or not. Secondly, it predicts the previously unknown concentrations of mer proteins in cells of each mercury phenotype. In addition, it challenges the hypotheses that the rates of uptake and volatilisation are always equal in resistant cells and that the plasmid copy number effects replicated by the model are caused by the saturation of MerT in the membrane. Thirdly, the model can guide the design of future experiments. This guidance can minimise the use of laboratory resources and will ensure that sufficient data are created for every parameter in the model under standardised conditions. Finally, the modelling has identified many areas for future biological research: the absolute concentrations of mer proteins, the significance of MerC and MerD, plasmid copy number effects and substrate inhibition, the three uptake processes (non-mer import, MerA transport, and non-MerA transport), the order of DNA + MerR + Hg2+ binding, the nature of toxicity, and the concentrations of mercury in each of the five cellular binding sites.
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Leszcynski, Robert A. "Determination of the Relationship Between Bacterial Coculturing, Antibiotic Resistance and Bacterial Growth". University of Dayton / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1591787505690696.
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I, D'Agostino. "Polyalkylguanidines: new weapons to tackle bacterial resistance". Doctoral thesis, Università di Siena, 2019. http://hdl.handle.net/11365/1070884.
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In this historical period known as the antibiotic crisis era, the ever faster rise of bacterial strains resistant to the clinically used antibiotics along with the scientific research silent gap in the antibacterial field is treating seriously to the worldwide public health. Hence, we urgently need to develop new antibacterials agents with an innovative mode of action, able to trick the mechanisms of the pathogen resistance.
In this alarming frame, aware of the antibacterial properties of guanidine moieties, Prof. M. Botta and his research group have evaluated the biological activity of a linear polyalkylguanidino series, synthesized for different medicinal purpose, toward a panel of bacterial microorganisms. Only one compound (1) emerged to have an interesting broad-spectrum antibacterial activity. Later, the serendipitous discovery that the test batch of compound 1 was actually a mixture of oligomers led us to identify the chemical structure of the main component, dimer 2, which was the responsible for the activity. From its scaffold, we designed and synthesized a small library of analogs to make some preliminary consideration on the pharmacophores with the aim of improving the selectivity index and studying the mode(s) of action.
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Cousin, Sydney Louis. "Macrolide resistance in Neisseria gonorrhoeae /". Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/5078.
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Nilsson, Annika. "Bacterial adaptation to novel selection pressures /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-192-X/.
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Giske, Christian G. "Carbapenem resistance in Pseudomonas aeruginosa /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-080-0/.
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Wood, Ryan. "Bacteria in Blood: Optimized Recovery of Bacterial DNA for Rapid Identification". BYU ScholarsArchive, 2020. https://scholarsarchive.byu.edu/etd/8147.
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Blood stream infections are challenging infections to rapidly diagnose. The current clinical diagnostic methods for blood stream infections require culturing the blood sample prior to identifying the bacteria and any resistance the bacteria may contain. Removing the culturing step from the bacterial identification process of a blood stream infection provides a significant reduction in the processing time. However, eliminating the culturing step shifts the difficulty from processing time to concentration, since clinical concentration levels can be as low as 10 CFU/mL in blood. This dissertation developed and evaluated many aspects of the process required to identify bacteria from a blood stream infection without culturing the bacteria. Two new methods of separating the bacteria from the blood cells were developed: inducing clotting using a centrifugal-sedimentation on a hollow disk, and filtering whole blood. Inducing clotting achieved 69\% bacterial recovery from 7 mLs of whole blood in 117 s. Filtering whole blood achieved 100\% bacterial removal from 5 mLs of whole blood in $\approx 90$ s, but the bacteria were difficult to remove from the filter. Bacterial removal from the filter after blood filtration was also investigated. At a very low bacterial concentration of 200 CFU/mL, a blood lysis solution of 3\% Tween 80 followed by a 3\% Pluronic F108 backflush solution achieved 60\% removal of the bacteria from the filter. In addition to developing two new methods, a previously developed technique using centrifugal-sedimentation on a hollow disk underwent a stability analysis in order to decrease the occurrence of mixing. This analysis yielded the development of the analytical solution to the Navier-Stokes equations for a two-fluid flow with a moving wall boundary and a free surface. The analysis also experimentally identified a stability boundary that was found to be in good agreement with the Kelvin-Helmholtz instability model. After exploring the methods to recover bacteria from blood, experiments were performed to identify a bacterial lysing solution that could lyse \textit{E. coli}, \textit{E. cloacae} and \textit{K. pneumoniae} bacteria. The best bacterial lysing solution consisted of incubating the bacteria with 1 mg/mL lysozyme for 10 min followed by the addition of 6 M GHCl and 1\% SDS. This solution obtained a 46\% DNA recovery. The DNA were then fragmented by ultrasound to reduce the segment length for DNA labelling. In addition to lysing and fragmenting the DNA, a microfluidic device was prototyped and tested for incorporating the lysing, capturing, releasing, and fragmenting of the DNA all on a single device. Whole experiments were performed which extracted the bacteria from the blood, removed and collected the DNA from the bacteria, and fragmented the DNA. The best overall recovery from an experiment performing the whole process was 26.8\%. The 26.8\% recovery was achieved with a 68\% recovery of the bacteria from spinning and a 54.1\% removal of bacteria from off of the filter and a 72.9\% recovery of the DNA from the bacteria.
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Reyes, Nikolle Susanne. "Marine bacterial isolates utilize unique mercury resistance mechanisms". Thesis, Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/25416.
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Gao, Feng. "Synthesis of aminoglycoside derivatives to combat bacterial resistance". Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18273.
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Aminoglycosides are broad spectrum antibiotics that act by binding to 16S rRNA of bacteria. The wide spread of aminoglycoside resistance threatens the use of these important medicines. Two general approaches can be used to address the aminoglycoside resistance problem. One is to derive the existing aminoglycoside antibiotics; the other is to develop inhibitors blocking resistance pathways.We developed a novel methodology to regio- and chemo-selectively derivatize unprotected aminoglycosides at the N-6' position, and used this method to prepare a series of amide-linked aminoglycoside-CoA bisubstrate analogs. These analogs are the first reported nanomolar inhibitors of AAC(6')-Ii, an aminoglycoside resistance-causing enzyme. They have been proved useful as mechanistic and structural probes to investigate the molecular mechanism of the catalysis by AAC(6')-Ii.Although the aminoglycoside-CoA bisubstrates are nanomolar inhibitors of AAC(6')-Ii, they are not active in cells due to their size and negative charges. A series of truncated aminoglycoside-CoA bisubstrates were next synthesized. These derivatives were used to determine key structure-activity relationships. One analog is discovered active against resistant strain in cells.Bisubstrate inhibitors containing sulfonamide, sulfone and sulfoxide linkers were synthesized and used as mechanistic probes to study mechanism of AAC(6')-Ii. Our results support the suggestion that AAC(6')-Ii may catalyze acetyltransfer without stabilization of the tetrahedral intermediate. Surprisingly, sulfide oxidation of the amide-linked bisubstrate dramatically improved inhibition of AAC(6')-Ii.Bisubstrates with linkers containing phosphoryl group (P=O) were proposed and synthesized, the biological results are under investigation. These molecules will facilitate investigations of the potential stabilization of the tetrahedral intermediate by the enzyme. Our efforts in this project also improved our chemical knowledge of phosphorus chemiLes aminoglycosides sont des antibiotiques à large spectre. Ils agissent en se fixant à l'ARN ribosomal 16S des bactéries et perturbent la synthèse protéique. L'extension rapide du phénomène de résistance aux aminoglycosides menace cependant leur efficacité. Parmi les différents mécanismes de résistance aux aminoglycosides, le plus important est la production d'enzymes inactivant l'antibiotique. Trois types d'enzymes impliquées dans ce mécanisme ont été identifiés, à savoir les aminoglycoside-N-acétyltransférases (AACs), les aminoglycoside-O-phosphoryltransférases (APHs) et les aminoglycoside-O-nucléotidyltransférases (ANTs). Deux approches peuvent être envisagées pour combattre ou contourner le phénomène de résistance. La première consiste à créer de nouveaux antibiotiques en modifiant des antibiotiques existant. L’autre implique le développement d'inhibiteurs capables de bloquer la résistance. Une nouvelle méthodologie pour la dérivatisation régio- et chimio-sélective d'aminoglycosides non protégés à la position N-6' a été développée. Cette méthode a ensuite été appliquée à la synthèse d'une série de bisubstrats aminoglycoside-coenzyme A. Ces analogues se sont avérés être de puissants inhibiteurs (resistance d'inhibition de l'ordre de la nanomole) de l'enzyme aminoglycoside 6'-N acétyltransférase Ii (AAC(6')-Ii), impliquée dans la résistance à de nombreux antibiotiques aminoglycosides. Plus particulièrement, ces molécules ont pu être co-cristallisées avec AAC(6')-Ii par nos collaborateurs, qui n'étaient à ce jour jamais parvenus à cristalliser cette enzyme avec un aminoglycoside. Les structures 3D ainsi obtenues ont permis d'obtenir de précieuses informations sur le site de fixation des aminoglycosides. Une deuxième génération d’inhibiteurs de l'AAC(6')-Ii a ensuite été synthétisée. Elle consistait en une série d'analogues tronqués de la première génération d'inhibiteurs. Ces ana
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Lloyd, Bryony Helen. "Bacterial resistance to tellurite and other metal ions". Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333673.
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Lindsay, Sharon. "Population antibiotic-resistance : a study of bacterial persistence". Thesis, University of Manchester, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528276.
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Ivanova, Aleksandra Asenova. "Nanomaterials for controlling bacterial pathogens and resistance occurrence". Doctoral thesis, Universitat Politècnica de Catalunya, 2022. http://hdl.handle.net/10803/673983.
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lnfectious diseases are the leading cause of death worldwide while the constantly raising antimicrobial resistance (AMR) is a major concern for the public health. During the infection establishment bacteria! pathogens communicate via expression of signaling molecules, controlled through a phenomenon called quorum sensing (QS). As a result of this, bacteria produce virulence factors and form resistant biofilms on living and non-living surfaces causing persistent infections. The infection complexity, especially in chronic diseases, requires the use of broad-spectrum antibiotics responsive for the appearance and the spread of drug resistant species. lnfections caused by antibiotic-resistant pathogens are associated with high morbidity, mortality, and huge economic burden. Unlike the decrease over the past three decades of the number of novel marketed antimicrobial drugs, the number of antibiotic resistant bacteria! strains steadily increases. Thus, there is an urgent need for development of alternative strategies to manage difficult-to-treat infections. This thesis aims at the engineering of advanced nano-enabled materials and nanostructured coatings for controlling bacteria! pathogenesis and resistance occurrence. To achieve this, biopolymers, antibiofilm and anti-infective enzymes. and inorganic compounds were nano-hybridized as altemative modalities to the conventional antibiotics. The nanoform was able to provide enhanced interaction with bacteria! cell membranes and easier penetration into biofilms, increasing the antimicrobial efficacy at lower dosages, while preventing from development of antimicrobial resistance. Additionally, specific targeting moieties increased the nanomaterial's interaction with the pathogens, avoiding the drug resistance appearance and cytotoxicity.
The first part ofthe thesis describes the functionalization of biologically inert nanoparticles (NPs) with membrane disturbing antimicrobial aminocellulose (AM) and biocompatible hyaluronic acid (HA) in an Lbl fashion for elimination of medically relevant pathogens. The generated nanoentities demonstrated high potential to inhibit the biofilm formation, without affecting the human cell viability.
Further, the Lbl technique was applied to decorate antimicrobial, but potentially toxic silver (Ag) nano-templates with biocompatible AM and quorum quenching (QQ) acylase in order to obtain safe antibacterial and antibiofilm nanomaterials. The deposition of acylase and AM on the Ag core interfered with the QS signaling and bacteria! pathogenesis, and enhanced the NPs interaction with the bacteria! membrane. The integration of a triple mechanisms of action in the hybrid nanoentities resulted in complete bacteria and biofilm eradication and improved biocompatibility ofthe AgNPs.
The thesís also describes the development of targeted nanocapsules (NCs) for selective elimination of Staphylococcus aureus. Herein, self-assembling nanoencapsulation technology using the biocompatible and biodegradable proteín zein was applied for the generation of zein NCs loaded with bactericida! oregano essential oil (EO). An antibody specifically targeting S. aureus was covalently grafted on the NCs surface. The obtained targeted NCs demonstrated antibacterial selectivity in a mixed bacteria! inoculum, and the treatment efficacy was validated in an in vitro coculture model of bacteria and mammalian cells.
Finally, high intensity ultrasonochemistry (US) process was employed for engineering of durable antibacterial/antibiofilm coating on urinary catheters. The simultaneous deposition of zinc oxide (ZnO) NPs anda matrix-degrading amylase enzyme improved the NPs adhesion on the silicone material, and prevented its bacteria! colonization and biofilm formation in vitro. The hybrid nanostructured coating delayed the occurrence of early onset urinary tract infections (UTls) and showed excellent biosafety in an in vivo animal model.Las enfermedades infecciosas son la principal causa de muerte en todo el mundo. Mientras que la resistencia a los antimicrobianos es una preocupación importante para la salud pública. Durante el establecimiento de la infección los patógenos bacterianos se comunican mediante la expresión de moléculas de señalización controladas mediante un fenómeno llamado detección de quórum (QS). Como resultado, las bacterias producen factores de virulencia y forman biopelículas resistentes que causan infecciones persistentes. Las infecciones causadas por patógenos resistentes a los antibióticos se asocian con una alta morbilidad mortalidad y una enorme carga económica. A diferencia de la disminución en las últimas tres décadas del número de nuevos medicamentos antimicrobianos comercializados el número de cepas bacterianas resistentes a los antibióticos aumenta constantemente. Por lo tanto existe la necesidad urgente de desarrollar estrategias alternativas para manejar infecciones diflciles de tratar. Esta tesis tiene como objeto de trabajo la ingenieria de materiales y recubrimientos avanzados nano estructurados para controlar la patogénesis bacteriana y la aparición de resistencias. Para lograrlo se combina polímeros anti biopelícula, enzimas anti infecciosas y compuestos inorgánicos como estrategias alternativas a los antibióticos convencionales. La nanoforma puede proporcionar una interacción mejorada con las membranas celulares bacterianas y una penetración más fácil en las biopelículas, aumentando la eficacia antimicrobiana en dosis más bajas al mismo tiempo que previene el desarrollo de resistencia antimicrobiana. Además las fracciones de orientación especificas aumentan la interacción del nano material con los patógenos evitando la aparición de resistencia al fármaco y la citotoxicidad.La primera parte de la tesis describe la funcionalización de nano partículas (NP) biológicamente inertes con aminocelulosa antimicrobiana (AM) perturbadora de la membrana y ácido hialurónico (HA) biocompatible en forma de LbL para la eliminación de patógenos médicamente relevantes. Las nanoentidades generadas demuestran un alto potencial para inhibir la formación de biopelículas sin afectar la viabilidad en las células humanas. Además, la técnica L.bL se aplica para decorar nanoplantillas de plata (Ag) antimicrobianas,pero potencialmente tóxicas con PNt biocompatible y acilasa de extinción de quórum (QQ) para obtener nanomateriales antibacterianos y anti biopelícula seguros. La deposición de acilasa y PNt en el núcleo de Ag interfiere con la señalización de QS y la patogénesis bacteriana y mejora la interacción de las NP con la membrana bacteriana. La integración de un triple mecanismo de acción en las nanoentidades híbridas da como resultado la erradicación completa de bacterias y biopelículas y una mejor biocompatibilidad de los AgNP. La tesis también describe el desarrollo de nanocápsulas dirigidas (NC) para la eliminación selectiva de Staphylococcus aureus. En este trabajo se aplica la tecnología de nanoencapsulación de autoensamblaje que utiliza la proteína Zeína biocompatible y biodegradable para la generación de NC de Zelna cargadas con aceite esencial de orégano bactericida.Un anticuerpo dirigido específicamente a S.aureus se injerta covalentemente en la superficie de las NC. Las NC dirigidos obtenidos demuestran selectividad antibacteriana en un inóculo bacteriano mixto.y la eficacia del tratamiento se valida en un modelo de cocultivo in vitro de bacterias y células de mamíferos.Finalmente, se emplea un proceso de ultrasonoqufmica de alta intensidad. Para la ingeniería de un recubrimiento antibacterlano/anti biopelícula duradero en catéteres urinarios. La deposición de NP de Óxido de Zinc y enzima amilasa que degrada la matriz.mejora la adhesión de las NP en el material de silicona evitando su colonización bacteriana y la formación de biopeliculas in vitro
Polímers i biopolímers
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Ouma, Christine. "REDUCING BACTERIAL RESISTANCE THROUGH BETTER ANTIBIOTIC PRESCRIPTION PRACTICES". VCU Scholars Compass, 2008. http://scholarscompass.vcu.edu/etd/1580.
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The objective of this study was to find a regression procedure that can better explain the relationship between patterns of antibiotic use and proportions of bacterial resistance. The sample for the study is comprised of 44 University Health System Consortium (UHC) member hospitals, and the data for antibiotic use and proportions of resistance are from the years 2002 to 2005. The hospitals are spread across the Northeast, South, Southwest, Midwest, and Northwest regions of the USA. Based on statistical analysis, MRSA continues to have the highest proportion of resistance among the bacteria examined and has increased significantly since 2002. The antibiotic use in the study was measured in indices called diversity indices. There were six such measures in the study. The study, first using ordinary least squares regression, did not find one single diversity index that adequately predicted the proportion of resistance. There were also concerns that the diversity indices could be measuring the same thing, and therefore all should not be used in the model. The correlations between the three general diversity indices were strong, positive, and linear. Likewise, the three Gram-negative indices were also positively correlated with one another. Multicollinearity diagnostics also showed that there were serious dependencies among general diversity indices. Given the multicollinearity results and the correlation coefficients for the indices, it can be concluded that all six indices should not be in the same model together. Logistic regression and weighted least squares regression using the logit transformation were also performed, and just like the ordinary least squares results, there was no one single diversity index or a combination of diversity indices that adequately predicted the proportion of resistance.
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Frost, Isabel. "The evolution of antibiotic resistance in bacterial colonies". Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:8dc07d49-0eb4-42fd-9a8e-ac3984eb587c.
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The continuing rise of antibiotic resistance is threatening a return to the world of pre-antibiotic medicine. Multi-drug resistant pathogens are already claiming lives and causing economic losses in developing and developed countries alike. We need, therefore, to understand what allows resistant strains to spread; what makes them evolutionarily competitive in and amongst other strains and species. The majority of laboratory studies of antibiotic resistance focus on simple growth in liquid culture. By contrast, microbes commonly grow as surface-associated communities, in which interactions between neighbouring cells have strong consequences for competition and evolution. My first goal was to understand how growth in such environments affects the success of a resistant strain. By competing an antibiotic resistant and susceptible strain of the pathogenic bacterium Pseudomonas aeruginosa, I found that growth in dense colonies on agar allowed a resistant strain to protect susceptible strains, to the extent that the susceptible strain may even prevail under antibiotic treatment. This effect was specific to a cooperative mechanism of antibiotic resistance, however; a β-lactamase enzyme that digests the antibiotics surrounding a resistant cell. A further, unexpected reason that susceptible cells could prevail was that they elongate under antibiotic treatment, allowing them to push shorter resistant cells aside in the competition for the growing edge of a colony. My work suggests that the rise of cooperative resistance mechanisms should be more easily suppressed than for non-social mechanisms. However, one major strategy to overcome antibiotic resistance is the use of antibiotic-adjuvants, drugs which inhibit a mechanism of antibiotic resistance. It is not clear if these adjuvants will tend to suppress or promote cooperative resistance mechanisms. I performed experiments to test the effects of inhibitory adjuvants on cooperative resistance. These revealed that the effects of adjuvants are varied. In liquid culture, an adjuvant inhibited resistance evolution, while, in colony experiments, it promoted resistance evolution by removing the cross protection of susceptible strains. Given the complexity and importance of antibiotic adjuvants, I developed an eco-evolutionary model to dissect these complexities associated with the combination of interacting microbial and molecular species. As in my experiments, the models identified conditions where an inhibitory adjuvant can increase selection for resistance. However, the theory also identifies scenarios for which adjuvants will delay resistance evolution by shutting down the associated evolutionary pathway. Broadening the modelling framework to include the stochastic effects of rare mutation, I found that early administration of adjuvant inhibitors can be a powerful way to suppress the emergence of antibiotic resistance. Microbial interactions are complex and affected by the growth environment. My thesis underlines that the study of antibiotic resistance will benefit from greater consideration of how bacteria interact and, more broadly, how their ecology and evolution determine the rise, or fall, of resistance.
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Griffith, James T. "The Influence of Antimicrobial use on Bacterial Resistance". ScholarWorks, 1992. https://scholarworks.waldenu.edu/dissertations/1395.
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Antimicrobial resistance is becoming an increasingly serious problem accompanied by relatively few studies examining the relationship between use and resistance. The present study undertakes a twenty year analysis of antimicrobial production and factors affecting antimicrobial use for a particular microorganism (Stp. faecalis)/antimicrobial agent (Cephalothin) combination. The period is inclusive of the market introduction of the agent and considerate of prescribing practices to the present time. The accumulated data reveal that there is indeed a relationship between total drug availability (medicinal, agricultural) and increased antimicrobial resistance. The data also suggest that national (or global) use changes would likely have a long term beneficial effect on the deteriorating circumstances surrounding microbial resistance to antimicrobial chemotherapeutic agents The methodology utilized includes analysis of primary historical data and graphical representation of indices derived from these data. A literature review examines the impact on antimicrobial resistance by historical duration of use, various mechanisms of resistance, non-medical uses of antimicrobial agents and clinical misuse.
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Riscado, Andreia Catarina Morgado. "Estudo das (multi)resistências bacterianas em clínica de animais de companhia". Master's thesis, Universidade de Évora, 2020. http://hdl.handle.net/10174/27834.
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O presente relatório de estágio pretende espelhar o trabalho desenvolvido, as
competências adquiridas e as aprendizagens consolidadas durante a realização do estágio
curricular na Clínica Veterinária - Clilegre, entre outubro de 2018 e janeiro de 2019.
O documento é composto por duas partes: na primeira descrevem-se as atividades
desenvolvidas e a casuística acompanhada; na segunda inclui-se uma monografia sobre a
problemática das resistências aos antimicrobianos, com apresentação e discussão dos
casos clínicos em que foi realizada colheita bacteriológica e teste de sensibilidade aos
antibióticos em animais de companhia.
A resistência bacteriana é um fenómeno natural que, aliado ao uso incorreto e
excessivo de antimicrobianos, tem favorecido a seleção de estirpes resistentes, tornandose num grave problema de saúde pública mundial.
Considerando a crescente proximidade entre animais de companhia e o Homem,
torna-se fundamental estudar o problema da resistência aos antimicrobianos,
sensibilizando profissionais de saúde para o uso adequado destes fármacos; Abstract: Study of (multi)resistant bacteria in companion animals clinics
This internship report intends to mirror the work developed, the skills acquired
and knowledge consolidation during the curricular internship at the Clilegre Veterinary
Clinic, from october 2018 to january 2019.
The document consists of two parts: the first part describes the activities
developed and the casuistic followed; the second includes a monography about
antimicrobial resistance, with the presentation and discussion of clinical cases in which
bacteriological isolation and antibiotic susceptibility testing were performed in
companion animals.
Bacterial resistance is a natural phenomenon that, combined with the incorrect and
excessive use of antibiotics, has favoured the selection of resistant strains, becoming a
serious public health problem worldwide.
Considering the growing proximity between companion animals and humans, it is
essential to study the problem of antibiotic resistance and raising awareness to health
professionals to the proper use of these drugs.
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Guest, Kerry Teresa. "Bacterial resistance to oxidising biocides : an assessment of resistance mechanisms and method development". Thesis, Cardiff University, 2016. http://orca.cf.ac.uk/94443/.
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Oxidising biocides are chemical agents grouped together by a similar mechanism of action. They are used in a range of settings to remove unwanted bacterial contamination. Bacterial resistance or decreased susceptibility to biocides was first observed over 70 years ago. The majority of bacteria exist as surface attached communities known as biofilms. Biofilms have a greatly reduced susceptibility to antimicrobials including biocides compared to their planktonic counterparts. For this reason, it is important to study the effect of antimicrobials on biofilms and planktonic cells. The aim of this project is to understand the mechanisms that allow survival and tolerance of bacteria exposed to oxidising biocides by using Salmonella as a representative enteric human pathogen. A range of methods were used to investigate the response of Salmonella enterica to sodium hypochlorite, hydrogen peroxide and peracetic acid. These included culture based methods such as inactivation kinetics and MICs. Flow cytometry, Hoescht assay and GFP reporters were also used to investigate the bacterial response to biocide in the planktonic state. Confocal microscopy was undertaken to investigate the effect of biocides on the structure of biofilms and determine the distribution of survivors within biofilms. Planktonic Salmonella were found to be more susceptible than intact biofilms, but once the biofilms were dispersed this protective effect was reduced. The protective effect was also seen in Salmonella Typhimurium SL1344 which is a poor biofilm former. Hydrogen peroxide exposure resulted in a change to cellular permeability, however this was not linked to efflux through the acrAB system. Flow cytometry demonstrated differential survival upon exposure to different biocides and identified potentially viable but non-culturable populations. Confocal microscopy demonstrated non-uniform distribution of survival of cells within a biofilm. An additional observation is that bacteria responded differently to each of the three biocides tested; there is not one consistent response to biocides with oxidising activity. This research shows the importance of using appropriate methods to test biocides. A key recommendation of this study is that all biocides should be tested against biofilms. This would give a better understanding of the efficacy of the biocides in more realistic and challenging conditions.
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Ivanova, Kristina Dimitrova. "Nanostructured coatings for controlling bacterial biofilms and antibiotic resistance". Doctoral thesis, Universitat Politècnica de Catalunya, 2017. http://hdl.handle.net/10803/405631.
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The accelerated emergence of drug resistant bacteria is one of the most serious problems in healthcare and the difficulties in finding new antibiotics make it even more challenging. To overcome the action of antibiotics bacteria develop effective resistance mechanisms including the formation of biofilms. Biofilms are bacterial communities of cells embedded in a self-produced polymeric matrix commonly found on medical devices such as indwelling catheters. When pathogens adopt this mode of growth on the surface, they effectively circumvent host immune defences and antibiotic therapy, causing severe and life threatening infections.
This thesis focuses on the development of advanced nanoscale materials and coatings for controlling bacterial biofilms and the emergence of drug resistance. To this end, acylase and amylase enzymes degrading essential for the biofilm growth components, were innovatively combined into hybrid nanocoatings to impart antibiofilm functionalities onto indwelling medical devices. Alternatively, ultrasound-assisted nanotransformation of antimicrobials was used as a tool for enhancing their antibacterial efficacy and overcoming the intrinsic drug resistant mechanisms in Gram-negative bacteria. These strategies offer new perspectives for prevention and treatment of biofilm infections, limiting the selection and spread of antibiotic resistance.
The first part of the thesis describes the building of enzyme multilayer coatings able to interfere with bacterial quorum sensing (QS) and prevent biofilm establishment on silicone urinary catheters. This was achieved by alternate deposition of negatively charged acylase and oppositely charged polyethylenimine in a Layer-by-Layer (LbL) fashion. The acylase-coated catheters degraded bacterial signalling molecules and inhibited the QS process of Gram-negative bacteria. These coatings also significantly reduced the biofilm growth on urinary catheters under conditions mimicking the real situation in catheterised patients, without affecting the human cells viability.
Acylase was further combined with the matrix degrading amylase enzyme into hybrid multilayer coatings able to interfere simultaneously with bacterial QS signals and biofilm integrity. The LbL assembly of both enzymes into hybrid nanocoatings resulted in stronger biofilm inhibition as a function of acylase or amylase location in the multi-layer coating. Hybrid nanocoatings with the QS inhibiting acylase as outermost layer reduced the occurrence of single and multi-species biofilms on silicone catheters in vitro and in an in vivo animal model.
The thesis also reports on the efficacy of nanomaterials for prevention and eradication of antibiotic resistant biofilms. Multilayer assemblies that contain in their structure and release on demand antibacterial polycationic nanospheres (NSs) were engineered on silicone surfaces. A polycationic aminocellulose (AC) conjugate was first transformed into NSs with enhanced bactericidal activity and then combined with hyaluronic acid to build bacteria-responsive layers on silicone material. When challenged with bacteria these multilayers disassembled gradually inhibiting both planktonic and biofilm modes of bacterial growth.
The same AC NSs were also covalently immobilised on silicone material using epoxy-amine conjugation chemistry. The intact NSs on the silicone material were able to inhibit bacterial biofilm growth, suggesting the potential of epoxy-amine curing reaction for generation of stable non-leaching coatings on silicone-based medical devices. Finally, ultrasound-assisted nanotransformation of penicillin G was used as a strategy to boost its activity towards bacteria. The efficient penetration of the NSs within a biomimetic membranes sustained the theory that they may reach the periplasmic space in Gram-negative bacteria and exert their bactericidal activity "unrecognised" as a threat by bacteria for selection of resistance.La rápida aparición de bacterias resistentes a fármacos es uno de los problemas más graves del sistema sanitario convirtiéndose en un gran reto encontrar nuevos antibióticos. Para superar la acción de los antibióticos, las bacterias utilizan diferentes mecanismos de resistencia incluyendo la formación de biopelículas. Las biopelículas son comunidades complejas de células bacterianas unidas por una matriz polimérica comúnmente encontradas en dispositivos médicos invasivos como los catéteres urinarios. Cuando los patógenos adoptan este modo de crecimiento en superficies, evitan eficazmente las defensas inmunitarias y el efecto de los antibióticos, causando infecciones. Esta tesis se centra en el desarrollo de nuevos materiales y recubrimientos nanoestructurados para el control de biopelículas bacterianas y la reducción de su resistencia a antibióticos. Por lo tanto, las enzimas acilasa y amilasa, capaces de degradar los componentes necesarios de las bacterias para formar biopelículas, se combinaron de forma innovadora en nanorecubrimientos híbridos para intervenir en el crecimiento de las biopelículas en dispositivos médicos permanentes. Además, la transformación de agentes antimicrobianos a forma "nano" se utilizó para mejorar su eficacia antibacteriana y superarlos mecanismos de resistencia a fármacos de las bacterias. Estas estrategias ofrecen nuevas perspectivas para el tratamiento de las infecciones relacionadas con biopelículas, limitando la selección y propagación de la resistencia bacteriana. La primera parte de la tesis describe la generación de recubrimientos multicapa de enzimas capaces de interferir con el sistema de comunicación bacteriana, denominado quórum sensing (QS) y prevenir la formación de biopelículas en el superficie de los catéteres urinarios. Esto se consiguió por deposición alternada de acilasa, cargada negativamente, y polietilenimina, cargada de manera opuesta, en la forma de capa a capa (LbL). Los catéteres recubiertos con acilasa inhibieron el proceso QS de bacterias Gram-negativas y redujeron significativamente el crecimiento de biopelículas en los catéteres urinarios en condiciones que imitaban la situación real en pacientes cateterizados. Adicionalmente, la acilasa se combinó con la enzima amilasa en recubrimientos híbridos capaces de interferir con las señales de comunicación entre bacterias y la integridad de la matriz de la biopelícula. El ensamblaje de las dos enzimas en recubrimientos híbridos dio lugar a una inhibición de la formación de biopelículas más fuerte en función de la localización de la acilasa o de la amilasa en la multicapa. Nanorecubrimientos con acilasa en la capa más externa redujo la formación de biopelículas en catéteres de silicona in vitro y en un modelo animal in vivo. La tesis también muestra la eficacia de nanomateriales para el control de biopelículas bacterianas. Las nanoesferas (NSs) antibacterianas, que contienen en su estructura multicapas ensambladas que se liberan bajo demanda, fueron depositados sobre silicona. Aminocelulosa (AC) se transformó primero en NSs obteniendo una mejor actividad bactericida y luego se combinó con ácido hialurónico para construir capas sensibles a las bacterias. Cuando se ponen en contacto con bacterias, estas capas se desmontan gradualmente inhibiendo las formas planctónicas y biopelículas. Los mismos ACNS también se inmovilizaron sobre silicona usando epoxi-amina. Las NSs intactas fueron capaces de inhibir el crecimiento de la biopelícula, lo que demuestra el potencial de la reacción de epoxi-amina para la generación de recubrimientos estables en dispositivos médicos de silicona. Finalmente, la nanotransformación de la penicilina G se utilizó como otra estrategia para aumentar la actividad del antibiótico hacia bacterias. Se demostró la a penetración efectiva de las partículas dentro de membrananas biomimeticas sugiera que las partículas alcanzan el espacio periplásmico en las bacterias y ejercen su actividad bactericida.
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Purewal, Amarjit S. "Bacterial genetic determinants specifying resistance to cationic antimicrobial agents". Thesis, University of Hull, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.253168.
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Bendall, J. B. "Bacterial resistance to antimicrobial agents in geriatric medical wards". Thesis, University of Nottingham, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381441.
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Osborn, Andrew Mark. "Evolutionary analysis of bacterial mercury resistance in natural environments". Thesis, University of Liverpool, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.262489.
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Knapp, Laura. "Bacterial resistance to biocides : development of a predictive protocol". Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/60862/.
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In the last 10 years biocides have been used increasingly and questions have been raised about their contribution to the reported increase in biocide and antibiotic resistance in pathogenic bacteria. The EU Biocidal Product Regulation (BPR) now requires information on the risk of resistance development in organisms targeted by the biocidal product. There is no current protocol available to predict the likelihood of bacteria becoming resistant to a biocidal product or biocides contained therein. This study aimed to identify useful markers of biocide resistance and develop a step-by- step protocol predictive of bacterial biocide resistance and antibiotic cross-resistance following biocide exposure. A range of experimental techniques with the potential to generate markers of biocide resistance were explored. These included minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC)/antibiotic susceptibility determination, flow cytometry, efflux activity measurements, outer membrane protein changes, real-time PCR and microarrays. Salmonella enterica serovar Typhimurium strains SL1344 and 14028S, and Burkholderia lata strain 383 were exposed to low concentrations of chlorhexidine gluconate and benzalkonium chloride as test biocides. Baseline and post-exposure data were then compared. Techniques used to understand any change in antimicrobial susceptibility were assessed in terms of practicality, cost and ease of use, and a step-by-step protocol was put together accounting for each of these factors. Increases in biocide MIC and MBC of up to 100 fold were observed in SL1344 and 14028S after exposure to both biocides. However these changes were not stable after subculture of surviving organisms in the absence of either biocide. No such dramatic changes were observed within B. lata. Up-regulation of efflux activity was observed as a result of CHG/BZC exposure and the efflux regulatory gene acrR underwent a >100 fold down-regulation in both Salmonella strains after CHG exposure. Flow cytometry experiments performed using SL1344 and 14028S indicated that at low CHG/BZC concentrations (0.0001 – 0.0004 %) greater than 50 % of the population were not killed and that these organisms could be sorted and further investigated to determine the mechanisms behind their survival. Reduction in the expression of two outer membrane proteins was observed in strain SL1344 after exposure to 0.0004 % CHG but further protein sequencing would be required to identify these. Changes in phenotype and genotype of biocide-exposed bacteria were identified using different experimental techniques. Some of these changes e.g. increased MIC/MBC values, altered antibiotic susceptibility, up-regulated efflux activity, alterations in the expression of specific genes and surviving organisms identified by flow cytometry represent useful markers of biocide resistance. A preliminary step by step protocol incorporating these techniques was successfully developed and allows for the rapid identification of biocide resistance and antibiotic cross-resistance as a result of biocide exposure, and will prove particularly useful in light of the recent changes to the BPR.
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Pietsch, Franziska. "Evolution of Antibiotic Resistance". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-265018.
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The emergence of antimicrobial resistance is a major global threat to modern medicine. The rapid dissemination of resistant pathogens and the associated loss of efficacy of many important drugs needs to be met with the development of new antibiotics and alternative treatment options. A better understanding of the evolution of resistance could help in developing strategies to slow down the spread of antimicrobial drug resistance. In this thesis we investigated the evolution of resistance to two important antibiotics, rifampicin and ciprofloxacin, paying special attention to the resistance patterns occurring with high frequency in clinical isolates. Rifampicin is a first-line drug in tuberculosis treatment and resistance to this valuable drug limits treatment options. Our work on rifampicin resistance helps to explain the extreme bias seen in the frequency of specific resistance mutations in resistant clinical isolates of M. tuberculosis. We identified an important interplay between the level of resistance, relative fitness and selection of fitness-compensatory mutations among the most common resistant isolates. Fluoroquinlones are widely used to treat infections with Gram-negatives and the frequency of resistance to these important drugs is increasing. Resistance to fluoroquinolones is the result of a multi-step evolutionary process. Our studies on the development of resistance to the fluoroquinolone drug ciprofloxacin provide insights into the evolutionary trajectories and reveal the order in which susceptible wild-type E. coli acquire multiple mutations leading to high level of resistance. We found that the evolution of ciprofloxacin resistance is strongly influenced by the mutation supply rate and by the relative fitness of competing strains at each successive step in the evolution. Our data show that different classes of resistance mutations arise in a particular, predictable order during drug selection. We also uncovered strong evidence for the existence of a novel class of mutations affecting transcription and translation, which contribute to the evolution of resistance to ciprofloxacin.
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Hopkins, J. M. "Mechanisms of cefotaxime resistance in Enterobacter SPP". Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384328.
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Simmons, Carla Stull. "Influence of copper on resistance of Lumbricus terrestris to bacterial challenge". Thesis, University of North Texas, 2000. https://digital.library.unt.edu/ark:/67531/metadc2602/.
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Earthworms, Lumbricus terrestris, were challenged orally and intracoelomically with two bacterial species, Aeromonas hydrophila and Pseudomonas aeruginosa, and mortality rates were observed. Neither were found to be particularly pathogenic at injected doses of up to 108 bacteria per earthworm. The influence of Cu++ (as CuSO4) on the earthworm's response to bacterial challenge was investigated by exposing earthworms to sublethal levels of Cu++ prior to bacterial challenge. Exposure at sublethal concentrations up to 3 m g/cm2 did not have a pronounced influence on host resistance to challenge as measured by earthworm mortality. Cu++ increased the earthworm's ability to agglutinate rabbit erythrocytes, indicating that Cu++ exposure caused coelomocyte death, autolysis and release of agglutinins into the coelom, possibly explaining resistance to bacterial challenge.
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Pränting, Maria. "Bacterial Resistance to Antimicrobial Peptides : Rates, Mechanisms and Fitness Effects". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-130168.
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The rapid emergence of bacterial resistance to antibiotics has necessitated the development of alternative treatment strategies. Antimicrobial peptides (AMPs) are important immune system components that kill microbes rapidly and have broad activity-spectra, making them promising leads for new pharmaceuticals. Although the need for novel antimicrobials is great, we also need a better understanding of the mechanisms underlying resistance development to enable design of more efficient drugs and reduce the rate of resistance development. The focus of this thesis has been to examine development of bacterial resistance to AMPs and the resulting effects on bacterial physiology. The major model organism used was Salmonella enterica variant Typhimurium LT2. In Paper I, we observed that bacteria resistant to PR-39 appeared at a high rate, and that the underlying sbmA resistance mutations were low cost or even cost-free. Such mutants are more likely to rapidly appear in a population and, most importantly, will not disappear easily once the selective pressure is removed. In paper II, we isolated protamine-resistant hem- and cydC-mutants that had reduced growth rates and were cross-resistant to several other antimicrobials. These mutants were small colony variants (SCVs), a phenotype often associated with persistent infections. One SCV with a hemC-mutation reverted to faster growth when evolved in the absence of protamine. In paper III, the mechanism behind this fitness compensation was determined, and was found to occur through hemC gene amplification and subsequent point mutations. The study provides a novel mechanism for reversion of the SCV-phenotype and further evidence that gene amplification is a common adaptive mechanism in bacteria. In Paper IV, the antibacterial properties of cyclotides, cyclic mini-proteins from plants, were evaluated. Cycloviolacin O2 from violets was found to be bactericidal against Gram-negative bacteria. Cyclotides are very stable molecules and may be potential starting points for development of peptide antibiotics.
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Vandal, Omar Haider. "Mycobacterium tuberculosis and the macrophage : host defenses and bacterial resistance /". Access full-text from WCMC:, 2008. http://proquest.umi.com/pqdweb?did=1428864551&sid=6&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Syed, Mohamed Ami Fazlin. "Pharmacokinetic and Pharmacodynamic Modeling of Antibiotics and Bacterial Drug Resistance". Doctoral thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-188306.
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Exposure to antibiotics is an important factor influencing the development of bacterial resistance. In an era where very few new antibiotics are being developed, a strategy for the development of optimal dosing regimen and combination treatment that reduces the rate of resistance development and overcome existing resistance is of utmost importance. In addition, the optimal dosing in subpopulations is often not fully elucidated. The aim of this thesis was to develop pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) models that characterize the interaction of antibiotics with bacterial growth, killing and resistance over time, and can be applied to guide optimization of dosing regimens that enhance the efficacy of mono- and combination antibiotic therapy. A mechanism-based PKPD model that incorporates the growth, killing kinetics and adaptive resistance development in Escherichia coli against gentamicin was developed based on in vitro time-kill curve data. After some adaptations, the model was successfully applied for similar data on colistin and meropenem alone, and in combination, on one wild type and one meropenem-resistant strain of Pseudomonas aeruginosa. The developed population PK model for colistin and its prodrug colistin methanesulfonate (CMS) in combination with the PKPD model showed the benefits for applying a loading dose for this drug. Simulations predicted the variability in bacteria kill to be larger between dosing occasions than between patients. A flat-fixed loading dose followed by an 8 or 12 hourly maintenance dose with infusion duration of up to 2 hours was shown to result in satisfactory bacterial kill under these conditions. Pharmacometric models that characterize the time-course of drug concentrations, bacterial growth, antibacterial killing and resistance development were successfully developed. Predictions illustrated how PKPD models based on in vitro data can be utilized to guide development of antibiotic dosing, with examples advocating regimens that (i) promote bacterial killing and reduce risk for toxicity in preterm and term newborn infants receiving gentamicin, (ii) achieve a fast initial bacterial killing and reduced resistance development of colistin in critically ill patients by application of a loading dose, and (iii) overcome existing meropenem resistance by combining colistin and meropenem
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Miller, Keith. "Role of bacterial hypermutators in the evolution of antimicrobial resistance". Thesis, University of Leeds, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275754.
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Lofton, Tomenius Hava. "Mechanisms and Biological Costs of Bacterial Resistance to Antimicrobial Peptides". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-284119.
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The global increasing problem of antibiotic resistance necessarily drives the pursuit and discovery of new antimicrobial agents. Antimicrobial peptides (AMPs) initially seemed like promising new drug candidates. Already members of the innate immune system, it was assumed that they would be bioactive and non-toxic. Their common trait for fundamental, non-specific mode of action also seemed likely to reduce resistance development. In this thesis, we demonstrate the ease with which two species of pathogenic bacteria, the gram-negative Salmonella typhimurium (S. typhimurium), and the gram-positive Staphylococcus aureus (S. aureus), can gain increased tolerance and stable resistance to various AMPs. By serially passaging each bacterial species separately under increasing AMP selection pressure we observed increasing AMP tolerance. Resulting in independent bacterial lineages exposed to four different AMPs (including a two-AMP combination) that exhibited 2 to 16-fold increases in MIC. Substantial cross-resistance between the AMPs was observed. Additionally, the S. aureus mutants were found to be cross-resistant to human beta-defensins 1, 2, 3, and 4. The LPS molecule, with mutations in the waaY, pmrB and phoP genes, was the principal target for S. typhimurium resistance development. The main target for S. aureus remained elusive. Reduced membrane potential was a common change for two of the mutants, but not for the others. All sequenced mutants had one or more mutations in various stress response pathways. Fitness of the resistant mutants was assayed by growth rate analysis and in vitro virulence factor testing (e.g. survival response to bile, superoxide, acidic pH). Furthermore an in vivo survival/virulence test involving a mouse competition experiment (S. typhimurium) and sepsis model (S. aureus) was performed. In the absence of AMPs there was often little or no fitness reduction in the mutants. Our results suggest that AMP resistance mechanisms do not irrevocably weaken either species with regard to virulence characteristics or survival within the host. In light of these findings, we suggest that the progression of therapeutic use of AMPs should proceed with great caution since otherwise we might select for AMP resistant mutants that are more resistant to our innate host defenses and thereby potentially more virulent.
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Jayawardana, Malini Anudya. "Genetic Mapping of Resistance to Bacterial Leaf Streak in Triticale". Thesis, North Dakota State University, 2017. https://hdl.handle.net/10365/28661.
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Bacterial leaf streak (BLS), caused by Xanthomonas translucens pv. undulosa (Xtu), is an important disease of wheat worldwide. The best way to control this disease in the field is the use of resistant cultivars. Although source of resistance is lacking in wheat, several triticale accessions have high levels of resistance. However, resistance in triticale has not be investigated. The main objective of this project was to map the BLS-resistance gene in triticale. A high density genetic linkage map was constructed in a triticale recombinant inbred line population covering all wheat and rye chromosomes. QTL mapping revealed a single locus on the chromosome 5R significantly associated with resistance to BLS. The resistance reaction of F1 hybrids indicated the dominance resistance. This is the first study to map a major resistance gene to BLS and will facilitate the introgression of this rye-derived BLS resistance into wheat genome through molecular marker-assisted chromosome engineering.
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Lee, Miseon. "THE DISCOVERY OF NOVEL MACROLIDE ANTIBIOTICS THAT ADDRESS BACTERIAL RESISTANCE". Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/436439.
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ChemistryPh.D.
Bacterial resistance is a formidable 21st-century global public health threat. If left unaddressed, we risk moving toward a “post-antibiotic era.” While resistance is a natural consequence of antibiotic use, the rate at which pathogenic bacteria have evaded multiple classes of drugs has markedly outpaced the introduction of new ones. New antibiotics are desperately needed to fill this void. Macrolides are one of the safest and most effective drug classes in medicine; however, resistance has compromised efficacy. To date, three generations have been developed with only the lattermost targeting bacterial resistance. Single next-generation macrolides will not keep pace with the inevitable onset of resistance; thus, there is a critical need to greatly accelerate the procurement of multiple future-generation antibiotics to tackle both current and future resistance mechanisms. My research is to meet this need by designing, synthesizing, and evaluating a novel, future-generation macrolide antibiotics that will serve as an armamentarium to be individually deployed on demand. In the previous research in Andrade group, we synthesized and evaluated various desmethyl ketolide analogs. The fact that 4-desmethyl telithromycin was fourfold less potent than telithromycin against A2058G mutants indicated replacing the 4-Me with hydrogen (i.e., desmethylation) to avoid a steric clash with the 2-amino group of G2058 was insufficient in rescuing bioactivity. Guided by MD simulation, we concluded a logical, superior alternative strategy was the replacement of the 4-Me group with one possessing a smaller vdW radius and capable of establishing favorable interactions with both wild-type and A2058G mutant ribosomes. Specifically, we reasoned that 4-fluoro solithromycin would be ideal candidate. The hypothesis was that the 4-fluoro moiety would engage in dipole-dipole interactions (C-F---H) with the exocyclic 2-amino group of guanine, which is based on accumulated evidence that strategic placement of organofluorine can strongly impact potency, selectivity, and physicochemical properties. In addition, the axially disposed of 4-fluorine would provide conformational stabilization from a gauche effect with the vicinal O5 group. The novel synthetic routes to unexplored desosamine analogs at the C3’-amino substituent to the macrolide antibiotic would play a role in bioactivity and resistance. Hofmann reaction was employed to execute the same 2,3-epoxide ring opening method without removing desosamine and re-glycosylating. This markedly reduces the steps, time, and cost involved in preparing novel desosamine-modified analogs. Significantly, this route enables the first synthesis of N,N’-disubstituted desosamine analogs from an epoxide, which was utilized to prepare novel analogs of clarithromycin. The application of in situ click chemistry toward the discovery of novel macrolide antibiotics first required the synthesis of suitable azide and aryl alkyne reactants. Alkyne partners were procured by commercial vendors or chemical synthesis. We targeted two logical, validated positions to tether the side chains, specifically N11 on the macrolactone and N3’ of desosamine. The first (N11) has been the most utilized. Moreover, extensive structure-activity relationships have revealed a four-carbon tether is ideal. Based on the solithromycin−E.coli X-ray structure, I designed, synthesized, and evaluated dehydro solithromycin, which possesses an (E)-alkene in the side-chain. The use of an unsaturated side chain would conformationally preorganize the bi-aryl side chain in order to pay the entropic penalty and thus favorably contribute to the overall binding. An insightful observation made from MD simulationed ribosomes bound with to solithromycin revealed that the interaction of the side-chain includes H-binding as well as π-stacking. The hypothesis was that employing tethered side-chains bearing motifs that maximize H-bonding and π-stacking would be superior antibiotics for treating resistant bacterial strains bearing erm¬-mediated N6 methyl and dimethylated ribosomes. To test this hypothesis, we developed various analogs with different alkynes by introducing different functional groups at the 3 and 5 positions on the aromatic ring. Another desosamine sugar modification is bis-azide. To date, the use of a two side chain strategy has not been reported. To access the requisite bis-azides, we employed a tactic the oxidative demethylation and alkylation of desosamine to afford bis-click solithromycin analogs.
Temple University--Theses
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Jobling, M. G. "Physical and genetic analysis of heavy metal resistance plasmids". Thesis, University of Liverpool, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372683.
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Hart, Mark Christopher. "Mercury resistance genes in a natural Bacillus population". Thesis, University of Liverpool, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366004.
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Liu, Xiulan. "Characterisation of antibiotic resistance gene clusters and their mobility within a collection of multi-drug resistant Salmonella spp". School of Biological Sciences - Faculty of Science, 2009. http://ro.uow.edu.au/theses/3043.
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One hundred and thirty-six Salmonella enterica strains, isolated from humans, animals, environmental and plant sources in Australia from 23 serovars, were examined for the streptomycin resistance gene strA and strB, the sulfonamide resistance gene sul2, and the tetracycline resistance gene tetA(A) and tetA(B). Thirteen strains were identified as containing the strA-strB genes located on the transposon Tn5393. S. enterica serovar Hadar accounted for 11 of these strains, 6 of which were isolated from humans and 5 were from ducks. This investigation is therefore the first report of the Tn5393 transposon being detected in bacterial strains from a human source in Australia.RSF1010 plasmids were identified and extracted from 4 S. enterica strains, and were further confirmed by restriction enzyme profiling using PstI, SspI and EcoRV. Small non-conjugative plasmid p9123 was extracted and characterised from 3 of the S. enterica strains and also confirmed by restriction enzyme digestion. An RSF1010-like plasmid was also identified in 3 of the strains. This plasmid was found to be approximately 2.6 kb larger than RSF1010, and possibly derived from the RSF1010 plasmid via insertion of the tetracycline resistance gene tetA(A) between strB and mobC genes.An IS26-strB-strA-sul2-repC-repA-IS26 antibiotic resistance region was identified in 33 S. enterica strains, among these were 23 serovar Typhimurium isolates, 8 serovar Bovismorbificans, 1 serovar Senftenberg and 1 isolate where the serovar could not be conclusively identified. The 23 Typhimurium strains were further characterised by PCR and Southern hybridisation analysis using a blaTEM gene probe. The analysis identified two classes of antibiotic resistance gene clusters. Eleven S. enterica serovar Typhimurium strains harboured an IS26-strB-strA-sul2-repC-repA-IS26-blaTEM-1-IS26 antibiotic resistance gene cluster and another 10 S. enterica serovar Typhimurium strains contained an IS26-strB-strA-sul2-repC-repA-IS26-blaTEM-1 gene cluster, without the IS26 element downstream of the blaTEM-1 gene. Two strains contain elements of these gene clusters but further investigation is needed to fully identify these.Further linkage PCR amplifications revealed that the IS26-strB-strA-sul2-repC-repA-IS26-blaTEM-1-IS26 antibiotic resistance gene cluster was possibly inserted into the 3P-CS of a class 1 integron (In4 type) and truncated the 3P-CS region. Three derivatives were identified, of which the dfrA5-intI1 type was most commonly found downstream of the blaTEM-1-IS26 region. Southern hybridisation analysis using an IS200 gene probe revealed that strains which contain different antibiotic resistance gene clusters also display different but related IS200 profiles.The antibiotic resistance gene clusters of 19 S. enterica serovar Typhimurium strains were transferred to an E. coli 294 Rifr recipient either by direct mating or triparental mating methods. These experiments confirmed that the antibiotic resistance gene clusters were located on conjugative or mobilisable plasmids. The antibiotic resistance gene clusters of 4 S. enterica serovar Typhimurium strains could not be transferred to the E. coli 294 Rifr recipient. These experimental results suggest that the antibiotic resistance gene cluster of IS26-strB-strA-sul2-repC-repA-IS26-blaTEM-1-IS26 might move as one genetic element between distinct plasmid backbones.
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Erlandsson, Marcus. "Surveillance of Antibiotic Consumption and Antibiotic Resistance in Swedish Intensive Care Units". Doctoral thesis, Linköping : Univ, 2007. http://www.bibl.liu.se/liupubl/disp/disp2007/med1019s.pdf.
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Paulander, Wilhelm. "Mechanisms of adaptation to the fitness cost of antibiotic resistance /". Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-149-4/.
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Davies, Sarah Elisabeth. "Development of antimicrobial resistance in Acinetobacter spp and methicillin-resistant Staphylococcus aureus". Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4388.
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Background: Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus (MRSA) represent the most worrying Gram-negative and Gram-positive nosocomial pathogens of the present age. They are of increasing concern in the clinical environment due to their multi-drug resistance and the dwindling therapeutic options available. A. baumannii is the most frequently isolated clinical species of the genus, and is able to rapidly acquire resistance. Hypermutators, most frequently deficient in mismatch repair (MMR) via defects in the mutS gene, have been associated with antimicrobial resistance in several bacterial populations. To date, however, the potential role of MMR-deficient mutators in the development of resistance in clinical Acinetobacter spp. has not been investigated. Biocides, most notably chlorhexidine (CHX), are increasingly used in the hospital environment to prevent bacterial spread. This has led to concerns about the development of reduced biocide susceptibility and associated antibiotic resistance in hospital bacterial populations, where there is frequent exposure to both of these factors. The effect of CHX upon defined clinical MRSA isolates is examined here. Methods: The mutS gene of clinical Acinetobacter spp. isolates with varying sensitivities was sequenced and compared to establish whether any variations were present. Mutation studies were performed on isolates by challenging them with ciprofloxacin to determine whether different mutS types correlated with any variation in their ability to develop significant fluoroquinolone resistance. The response of clinical MRSA isolates to a range of CHX concentrations was examined with susceptibility testing methods, and effects were compared with standard strains. Determination of post-exposure minimum inhibitory concentrations (MICs) of a range of antibiotics enabled evaluation of whether exposure to CHX had an effect on susceptibility to antibiotics. Results: Variation was observed in the mutS gene of clinical Acinetobacter spp. isolates, with greater homology observed as resistance increased. A highly conserved and previously unreported amino acid sequence was discovered in resistant isolates. Nonresistant isolates with this ‘R-type’ mutS sequence appeared to have a greater ability to develop significant ciprofloxacin resistance. Clinical MRSA isolates had varying susceptibility to CHX, and there were differences in the susceptibility of standard strains compared to clinical isolates. CHX residues exerted a prolonged minimal inhibitory effect, and several increases in antibiotic MICs following CHX exposure were observed. Conclusions: The correlation of the mutS sequence with mutation ability suggests that defects in the mutS gene may have a role to play in the ability of certain Acinetobacter spp. to rapidly acquire resistance. This could have implications for the treatment of Acinetobacter spp. infections, and may enable quick determination of which clinical isolates have the potential to develop clinically significant resistance. Incomplete eradication due to the prolonged minimal effect of CHX residues may act as a selective pressure in the hospital environment, allowing survival of reduced susceptibility MRSA isolates. Increases in antibiotic MICs following CHX exposure is of grave concern for the future of biocide usage.
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Lewandowski, Eric Michael. "Structure Based Drug Design Targeting Bacterial Antibiotic Resistance and Alzheimer's Disease". Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5982.
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Structure based drug design is a rapidly advancing discipline that examines how protein targets structurally interact with small molecules, or known inhibitors, and then uses this information to lead inhibitor optimization efforts. In the case of novel inhibitors, protein structural information is first obtained via X-ray crystallography, NMR studies, or a combination of both approaches. Then, computational molecular docking is often used to screen, in silico, millions of small molecules and calculate the potential interactions they may have with the target protein’s binding pocket, in hopes of identifying novel low affinity inhibitors. By examining the interactions these small, low affinity, inhibitors have with the binding pocket, optimization efforts can be focused on maximizing interactions with “hot spots” within the pocket, thus leading to larger, high affinity inhibitors. A similar optimization technique can also be applied to known inhibitors. By examining the interactions of a known inhibitor with the binding site, new compounds can be designed to target “hot spots” in the binding pocket using the known inhibitors core structure as a starting point. The affinity of the newly designed compounds can then be compared to the affinity of the original inhibitor, and further rounds of optimization can be carried out. While simple in design, there are many challenges associated with structure based drug design studies, and there is no guarantee novel inhibitors will be found, but ultimately, it is an extremely powerful methodology that results in a much higher hit rate than other, similar, techniques. The work herein describes the use of structure based drug design to target several different proteins involved in bacterial antibiotic resistance, and a protein that has been implicated in the development of Alzheimer’s disease.
The goal of the first project was to design a new PBP inhibitor based upon an existing scaffold, and to better understand the binding mechanism and molecular interactions between penicillin binding proteins and their inhibitors. PBPs are a group of proteins that catalyze the last steps of bacterial cell wall formation, and are the targets of the β-lactam antibiotics. Two compounds were designed which conjugated a ferrocene or ruthenocene group to 6-aminopenicillinic acid, and their antibiotic properties were tested against a range of bacterial strains. To get a better understanding of how the 6-APA organometallic compounds interacted with the PBP active site, a CTX-M-14 β-lactamase model system was used for X-ray crystallographic studies. CTX-M-14 was chosen as its active site shares many key catalytic features with PBPs, and it easily, and reproducibly, yields crystals capable of diffracting to sub-atomic (< 1.0 Å) resolution.
I determined a 1.18 Å structure of 6-APA-Ru in complex with CTX-M-14 E166A β-lactamase and was able to gain unprecedented details of the interactions of the ruthenocene group with the CTX-M active site. This structure also revealed that the compound bound in the CTX-M active site was actually the decarboxylated and hydrolyzed product, which was the first time a decarboxylated product had been captured in the CTX-M active site. A second, 0.85 Å, structure of CTX-M in complex with 6-APA-Ru was determined and shed light on how the hydrogen bonding network in the CTX-M active site changes in response to the 6-APA-Ru product binding. A final, 1.30 Å, structure captured the carboxylated and hydrolyzed 6-APA-Ru product in complex with CTX-M, which was the first time the carboxylated product had been captured in the CTX-M active with the catalytic Ser70 residue intact. The results show the potential of the ruthenocene group in improving antibiotic potency, and help to better elucidate the changes that occur in the CTX-M active site upon inhibitor binding, while at the same time, telling us what changes could occur in the active site of PBPs.
The next project was focused on novel inhibitor discovery against several different PBPs. PBPs have been successfully inhibited by β-lactam antibiotics for decades, but the alarming rise of bacteria resistant to these antibiotics has placed increased urgency on the discovery of novel PBP inhibitors. A fragment based molecular docking approach was employed to virtually screen millions of small compounds for interactions with the targeted active sites, and then high scoring compounds were selected for visual inspection and inhibitory testing. Virtual screening was first done against Staphylococcus aureus monofunctional transglycosylase, a type of PBP. MTG provided a good binding pocket for virtual screening, but proved challenging to purify and crystallize. However, through great effort MTG crystals were eventually obtained. After repeated rounds of virtual screening against MTG, multiple compounds were selected for inhibition testing, and testing is currently ongoing. Virtual screening was also done against Pseudomonas aeruginosa PBP5 and PBP1a. Purification and crystallization of these proteins proved to be easier than MTG, and both yielded diffraction quality crystals.
The final project focused on virtual screening against a protein implicated in the development of Alzheimer’s disease, Slingshot Phosphatase 1. The brains of AD patients have been found to contain elevated levels of active Cofilin, and these elevated levels of active Cofilin may lead to the overproduction of amyloid β. Aβ overproduction, and its resulting accumulation, is believed to be one of the pathways that lead to AD symptoms. Cofilin is activated when it is dephosphorylated by SSH1, and inhibiting this activation may decrease the production of Aβ and the development of AD symptoms. There is no known structure of SSH1, so to perform virtual screening a SSH1 homology model was constructed using the homolog SSH2 as a starting point. Virtual screening was then performed using the SSH1 homology model and many compounds were selected for inhibition testing. Initial testing found several compounds that could prevent Cofilin dephosphorylation at levels > 10μM. However, three compounds were found to be exceptionally active, and could prevent Cofilin dephosphorylation at both 1 and 10 μM. One of these three compounds was tested directly against purified SSH1 and found to inhibit its activity, and reduce Aβ production. Crystallization of purified SSH1, and SSH2, was attempted in order to get complex structures with the three best compounds. SSH2 crystals were obtained which diffracted to 1.91 Å, and several initial hits were found for SSH1. Optimization of crystals for both proteins is currently ongoing. The SSH1 inhibitor, along with the two other highly active compounds, provides an excellent starting point for the development of highly potent SSH1 inhibitors.
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Oliver, Kerry M. "The role of pea aphid bacterial symbionts in resistance to parasitism". Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1031%5F1%5Fm.pdf&type=application/pdf.
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Yan, Xuxu. "Synthesis and biological study of aminoglycoside derivatives to overcome bacterial resistance". Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96824.
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Aminoglycosides are broad-spectrum antibiotics that target the A-site of bacterial 16S ribosomal RNA. Their use, however, is increasingly threatened by the rapid spread of resistance. One of the most common determinants of aminoglycoside resistance in bacteria is the expression of a class of enzymes known as aminoglycoside 6′-N-acetyltransferases (AAC(6′)s). These enzymes use acetylcoenzyme A (AcCoA) to acetylate most aminoglycosides at the 6′-NH2, thus decreasing their affinity for RNA and leading to bacterial resistance. One strategy pursued by the Auclair research group to overcome aminoglycoside resistance is to develop AAC(6′) inhibitors. Chapter 2 of this thesis describes enzymatic studies with the group's first generation of inhibitors, aminoglycoside-CoA bisubstrates and truncated analogs. The bisubstrates exhibited potent nanomolar competitive inhibition of the Enterococcus faecium isoform AAC(6′)-Ii and proved to be useful mechanistic and structural probes. They did not however show activity in cells. Enzymatic studies with truncated bisubstrates allowed extensive SAR studies and led to the discovery of a second generation of inhibitors, one of which is capable of blocking aminoglycoside resistance in cells expressing AAC(6′)-Ii. To improve the potency of this compound, a series of derivatives with various amide groups replacing the ester functionality were synthesized. It was hypothesized that this modification would increase potency and biological stability. To our surprise however these small changes had a negative impact on the interaction between the inhibitors and AAC(6′)-Ii. Chapter 3 describes our second approach to counter aminoglycoside resistance, which involved the synthesis of new aminoglycosides designed to be active against resistant bacterial strains. A series of neamine N-6′-acylated derivatives were designed to retain the hydrogen bonding ability of 6′-N to RNA, yet disrupt binding to AAC(6′)-Ii. Some of these compounds showed moderate but not clinically relevant activity in cells.Finally, the third approach elaborated in Chapter 4 is to design prodrugs with dual, resistance inhibition and antibacterial activities. The goal was to develop aminoglycoside N-6′ derivatives as prodrugs that were expected to be extended to bisubstrate analogs by the CoA biosynthetic enzymes in bacteria. The resulting bisubstrates were expected to not only block aminoglycoside resistance via AAC(6′) inhibition, but to also kill bacteria by blocking the fatty acid biosynthetic pathway. A small series of aminoglycoside derivatives was thus synthesized. Unexpectedly none of them showed direct antibacterial activity. Preliminary biological studies however suggest that even in the absence of in vitro AAC(6′) inhibition, these molecules can potentiate the activity of aminoglycosides against an aminoglycoside resistant strain. To our knowledge they are the first reported prodrugs able to block aminoglycoside resistance in cells.Les aminoglycosides sont des antibiotiques à large spectre qui ciblent le site A de l'ARN ribosomique 16S dans la bactérie. Leur usage, par contre, est de plus en plus menacé à cause de l'étendue rapide de la résistance contre les aminoglycosides. La classe d'enzyme aminoglycoside-6′-N-acétyltransférases (AAC(6′)) est l'un des détermiants de résistance le plus commun. Ces enzymes utilisent acétylcoenzyme A (AcCoA) pour acétyler plusieurs aminoglycosides à la position 6′-NH2, ce qui diminue leur affinité pour l'ARN et la résistance en résulte. Une des stratégies privilégiée par notre groupe de recherche pour combattre la résistance aux aminoglycosides est décrite au Chapître 2. Elle consiste à développer des inhibiteurs contre AAC(6′). La première génération d'inhibiteurs, des bisubstrats de type aminoglycoside-CoA, a démontré une inhibition compétitive nanomolaire in vitro. Quoiqu'ils fussent utiles comme éléments de recherche structurale et mechanistique, ils ne démontrent aucune activité biologique. L'étude subséquente d'analogues de bisubstrats raccourcis a permis d'établir des relations structure-activité et a mené à la découverte d'une seconde génération d'inhibiteurs, incluant une molécule avant la capacité de bloquer la résistance aux aminoglycosides dans les cellules bactériennes exprimant l'AAC(6′)-Ii. Pour améliorer l'efficacité de ce composé, nous avons synthétisé une troisième génération d'inhibiteurs dont l'ester a été remplacé par divers groupements amide. L'hypothèse était que l'amide serait plus stable, menant à des composés plus stables et plus efficace, biologiquement parlant. À notre surprise, ces modifications ont diminué de façon significative l'interaction entre les inhibiteurs et AAC(6′)-Ii. Le troisième chapître de cette thèse explore une autre stratégie pour contrer la résistance envers les aminoglycosides. Elle vise à créer des agents antibactériens actifs contre les bactéries résistantes. Une série de dérivés de néamine acylés à la position 6′-N ont été envisagés afin de retenir l'habileté de l'amine 6′ à faire un lien hydrogène avec l'ARN tout en perturbant l'adhérance envers l'AAC(6′). Certains composés ont démontré des propriétés antibactériennes modérées dans les cellules mais sans potentiel clinique. Enfin, notre troisième approche vise à créer des pro-médicaments possédant à la fois la capacité de contrer la résistance ainsi que des propriétés antibactériennes. Notre but était de développer des dérivés d'aminoglycoside qui seraient transformés en analogues de bisubstrats par les enzymes bactériennes impliquées dans la biosynthèse de CoA. Les bisubstrats résultant pourraient non seulement bloquer la résistance en inhibitant l'enzyme AAC(6′), mais aussi avoir des propriétés antibactériennes en affectant la biosynthèse des acides gras. Une série de ces dérivés d'aminoglycosides a été synthétisée et aucun produit ne montre d'activité antibacterienne. Par contre, des résultats préliminaires suggèrent que même si ces molecules n'inhibitent pas l'enzyme AAC(6') purifiée, elles possèdent l'habileté d'augmenter l'action des aminoglycosides dans les bactéries résistantes. Selon nos connaissances, il s'agit des premiers pro-médicaments capablent de bloquer la resistance aux aminoglycosides dans les cellules.
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De, Pieri Lucrezia A. "A study of light scattering and heat resistance of bacterial spores". Thesis, University of Nottingham, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293146.
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Wong, Ruth. "Structure and function of multidrug efflux systems in bacterial antibiotic resistance". Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612755.
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Biesecker, Steven. "THE ROLE OF BACTERIAL AMYLOID FIBRILS IN ESCHERICHIA COLI COMPLEMENT RESISTANCE". Master's thesis, Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/174200.
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Microbiology and ImmunologyM.S.
Strains of Escherichia coli may exist as a beneficial human commensal or a pathogen capable of causing morbidity and mortality. Of the E. coli which causes human disease, many strains which cause bacteremia have been identified as possessing virulence factors which make them more resistant to the complement system. The bacterial amyloid fibril, curli, functions in bacterial adherence and the formation of biofilm. Curli-producing parental and curli-deficient mutant E. coli was compared in its survival to human complement, using in vitro serum sensitivity assays. Results showed an increase in the survival of curli-producing E. coli, which suggested that curli defends against complement killing. An in vivo murine model of E. coli-induced sepsis demonstrated that curli-producing bacteria also survived significantly better in the blood of mice. Immunostaining and flow cytometry was done to determine if parental and mutant strains of E. coli differentially bind to complement components C1q and C3. Results demonstrated that curli increases binding of C1q, but does not affect C3 binding. Blocking the classical pathway suggested that, in these assays, the classical pathway was the major contributor to complement activation and curli inhibits its activity. In addition, blocking the alternative pathway supported that the classical pathway was the main mechanism for complement activation and suggested that curli is not involved in protecting E. coli against alternative pathway activation. Results of this study conclude that curli defends E. coli against complement killing via inhibition of the classical complement pathway.
Temple University--Theses
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May, Megan Katherine. "Characterizing bacterial antibiotic resistance, prevalence, and persistence in the marine environment". Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122524.
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Thesis: Ph. D., Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution), 2019Cataloged from PDF version of thesis.
Includes bibliographical references.
Antibiotics are naturally occurring chemicals in bacteria that were recently discovered and utilized by humans. Despite a relatively short time of use, anthropogenic use of antibiotics has increased natural levels of antibiotic resistance, which has caused a looming antibiotic resistance crisis, where antibiotics may not work. Understanding resistance patterns is critical to allow for continued therapeutic use of antibiotics. While resistance is often thought of in hospitals, antibiotics and antibiotic resistance genes from human activity are disposed of into nature where they are able to interact with naturally occurring antibiotics and resistance. In this dissertation, I examine the ocean as an understudied region of the environment for antibiotic resistance. The ocean represents an area of human activity with recreation and food consumption and it is an enormous region of the planet that is affected by both land and sea activities.
In Chapter 2, I explore the policies that have contributed to the antibiotic resistance crisis. I offer explanations of market and political failures that contributed to the situation, areas for growth in terms of assessing scientific knowledge, and finally, recommendations for mitigating antibiotic resistance. In Chapters 3 and 4, I collected individual bacterial cultures from Cape Cod, MA beaches to assess the phenotypic response to antibiotic resistance. I show that 73% of Vibrio-like bacteria and 95% of heterotrophic bacteria (both groups operationally defined) are resistant to at least one antibiotic. These results indicate that antibiotic resistance is prevalent and persistent on beaches over both spatial and temporal scales. In Chapter 5, I used metagenomics to assess the abundance and types of resistance genes at coastal impacted Massachusetts sites. I found that, even in sites that seem distinct in terms of anthropogenic impact, prevalence of resistance remained the same.
Finally, in Appendix A, I examined part of the TARA Ocean dataset for prevalence of antibiotic resistance genes across the world's ocean. Here, I found that there are distinctions between different ocean biomes based upon antibiotic, metal, and mobile genetic elements. This dissertation has increased the understanding of temporal and spatial dynamics of antibiotic resistance in the coastal and open ocean.
"This work has be funded by the National Science Foundation Graduate Research Fellowship under Grant No. 1122374 and a Martin Fellows for Sustainability Fellowship (both to MKM). Grants from Woods Hole Oceanographic Institution from the Coastal Ocean Institute, Grassle Family Foundation, Hill Family Foundation, and Biology Department also supported this work"--Page 6
by Megan Katherine May.
Ph. D.
Ph.D. Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution)