Dissertations / Theses on the topic 'Multidrug resistance'
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1
Bolhuis, Hendrik. "Multidrug resistance in Lactococcus lactis." [S.l. : [Groningen] : s.n.] ; [University Library Groningen] [Host], 1996. http://irs.ub.rug.nl/ppn/153237724.
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Di, Nicolantonio Federica. "Multidrug resistance in solid tumours." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1354622/.
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Introduction: Most cancers show heterogeneity of response to chemotherapy. This may be due in part to the differential expression of drug resistance proteins and the molecular targets of the drugs concerned. Methods: An ex vivo ATP-based Tumour Chemosensitivity Assay (ATP-TCA), immunohistochemistry and quantitative RT-PCR have been used to assess the chemosensitivity and resistance of a variety of solid tumours and cell lines. Results: (a) Melanoma cell lines showed higher chemosensitivity than tumour-derived cells, partially reversible by lowering the serum concentration, and hence the proliferation rate of the cells. (b) Studies of retinoblastoma samples confirmed that this malignancy is susceptible to cytotoxic drugs of all types, though multidrug resistance may occur in some cases. (c) The ATP-TCA was used to study the activity of high-dose doxorubicin in combination with other cytotoxic agents in ovarian adenocarcinoma samples. The combination of liposomal doxorubicin + vinorelbine was selected for further development. (d) A number of experimental drugs with varying sensitivity to resistance mechanisms were also assessed. One drug, XR5944, has entered phase I/II clinical trials during the course of this project, and the data have provided clinical indications. (e) An inhibitor of multi-drug resistance, tariquidar, has been tested in combination with doxorubicin, vinorelbine or paclitaxel, and has been shown to reverse this resistance. (f) Molecular studies have determined the expression of topoisomerases and drug transporters in tumour cells before and after exposure to chemotherapeutic agents. P-gp expression has been found to be a determinant of sensitivity to a certain number of drugs. Conclusion: The results suggest that drug resistance contributes to heterogeneity of chemosensitivity in many solid tumour types, as well as other mechanisms. Reversal of such resistance may benefit a subset of patients undergoing chemotherapy.
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Clark, Fiona S. "Multidrug resistance in Candida albicans." Thesis, University of Aberdeen, 1994. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU073141.
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Azole-resistance in Candida albicans is becoming common and is associated with the widespread prophylactic use of azoles. Resistance to one azole is usually associated with resistance to other structurally dissimilar azoles. C.albicans is also inherently resistant to a wide range of eukaryotic inhibitors such as cycloheximide and gentamycin. Certain studies have shown that azole-resistance in some strains of C.albicans is associated with alterations in the cell membrane. This project has sought to determine whether azole-resistance in C.albicans strain 3302 was due, at least in part, to a multidrug resistance mechanism. An assay was developed using the fluorescent dye Rh123 to measure P-glycoprotein like activity. Active efflux of Rh123 has been shown to correlate with P-glycoprotein activity in a number of organisms. Results from this assay suggest that an energy-dependent efflux mechanism for Rh123 is present in azole-resistant strain 3302 but not in azole-sensitive strain 3153. The P-glycoprotein inhibitor, reserpine, inhibited Rh123 efflux. However, azoles did not appear to compete with Rh123 for efflux in the azole-resistant strain 3302, suggesting that azole-resistance in this strain is not mediated by a P-glycoprotein like mechanism. Southern analysis showed that sequences homologous to MDR genes existed in C.albicans. A PCR strategy was used to clone gene fragments containing the Walker motif which is found in MDR genes.
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Norris-Cervetto, Edward. "Glycolipids and multidrug resistance in cancer." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419326.
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Bellamy, William Tracey. "Mechanisms of doxorubicin resistance in multidrug resistant human myeloma cells." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184448.
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Multidrug resistance is a phenomenon associated with the emergence of simultaneous cross-resistance to the cytotoxic actions of a wide variety of structurally and functionally unrelated antineoplastic agents. One of the agents to which cross-resistance is commonly observed is doxorubicin, a commonly used antineoplastic. Studies were undertaken to determine the mechanism of doxorubicin resistance in multidrug resistant 8226 human myeloma cells. When sensitive and resistant cells were exposed to the same extracellular concentration of doxorubicin there was a decrease in the quantity of DNA lesions in the resistant subline which corresponded to a decrease in doxorubicin accumulation. When the extracellular concentration of drug was adjusted to yield equivalent intracellular levels these differences were removed. Studies utilizing an isolated nuclei system revealed no differences in the formation of DNA lesions between the sensitive and resistant cells when exposed to the same concentration of drug. Studies were undertaken to determine if the resistant subline had an increased capacity to detoxify doxorubicin via glutathione-based enzyme systems. The activities of glutathione-s-transferase and glutathione peroxidase were not found to be elevated in the resistant subline. There was a significant elevation in the nonprotein sulfhydryl content of the resistant cells as compared to the drug-sensitive line. This elevation was unstable in the absence of doxorubicin, displaying a steady decline until reaching baseline levels found in the sensitive cells. The decrease in NPSH content in the resistant line was not accompanied by an alteration in doxorubicin resistance. Thus, it appears that glutathione-based enzymatic detoxification is not causally related to doxorubicin resistance in 8226 human myeloma cells. Verapamil, an agent shown by previous studies to modulate doxorubicin resistance, led to an increase in the formation of doxorubicin-induced DNA lesions in the resistant cells secondary to an increase in intracellular drug accumulation. It had no effect on doxorubicin-induced DNA lesions or drug accumulation in the sensitive cells. Verapamil thus appears to be reversing doxorubicin resistance by increasing drug accumulation and thereby enhancing DNA damage. Under these circumstances there was a good correlation between doxorubicin accumulation, DNA damage, and cytotoxicity in the 8226 cells. The conclusion is drawn that drug accumulation accounts for the majority of doxorubicin resistance in the 8226 human myeloma cell line.
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Egger, Michael. "Inhibition of ABC transporters with multidrug resistance." kostenfrei, 2009. http://epub.uni-regensburg.de/13404/.
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Atalay, Mustafa Can. "Multidrug Resistance In Locally Advanced Breast Cancer." Phd thesis, METU, 2004. http://etd.lib.metu.edu.tr/upload/12604991/index.pdf.
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ABSTRACT
MULTIDRUG RESISTANCE IN LOCALLY ADVANCED BREAST CANCER
ATALAY, Mustafa Can
Ph. D., Department of Biotechnology
Supervisor: Prof. Dr. Ufuk GÜNDÜ
Z June 2004, 70 pages Breast cancer is the most frequently detected cancer among women. Early diagnosis leads to long term survival when the patients are treated with surgery, radiotherapy, chemotherapy, and hormone therapy. Unfortunately, advanced disease could still be encountered in some patients resulting in a poorer prognosis. The primary treatment modality is chemotherapy for this group of patients. Drug resistance is a serious problem resulting in the use of different drugs during chemotherapy and knowing the possibility of resistance before initiating first line chemotherapy may save time and money, and most importantly, may increase patient&rsquo
s survival. Therefore in this study, multidrug resistance is studied in locally advanced breast cancer patients. The breast tissues obtained from 25 patients both before and after chemotherapy were examined for drug resistance. Reverse transcriptase polymerase chain reaction was used for the detection of mdr1 and mrp1 gene expression. In addition, immunohistochemistry technique was used for P-glycoprotein and MRP1 detection. JSB-1 and QCRL-1 monoclonal antibodies were utilized to detect P-glycoprotein and MRP1, respectively. Five patients were unresponsive to chemotherapy. In four of these patients mdr1 gene expression was induced by chemotherapy where as the fifth patient initially had mdr1 gene expression. In addition, Pgp positivity was detected in 9 patients after chemotherapy. Both the induction of mdr1 gene expression (p<
0.001) and Pgp positivity (p<
0.001) during chemotherapy were significantly related with clinical response. On the other hand, mrp1 gene expression and MRP1 positivity were detected in 68% of the patients before the therapy. After chemotherapy, mrp1 expression increased to 84%. Although 80% of the clinically unresponsive patients had mrp1 gene expression, the relation between mrp1 expression and clinical drug response was not strong. Thus, it can be concluded that in locally advanced breast cancer mdr1 gene expression during chemotherapy contributed to clinical unresponsiveness. However, mrp1 gene expression did not correlate strongly with the clinical response. When RT-PCR and immunohistochemistry methods are compared in terms of detection of drug resistance, it seems that both methods gave similar and reliable results.
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Rawson, Emma. "Int6-induced multidrug resistance in S. pombe." Thesis, University of Oxford, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436992.
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Findlay, Jacqueline. "Klebsiella pneumoniae : a progression to multidrug resistance." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6473.
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Klebsiella pneumoniae is a common cause of nosocomial and community-acquired infections, and the increasing incidence and prevalence of antibiotic resistant strains is proving to be particularly problematic to clinicians. K. pneumoniae is capable of employing a multitude of mechanisms by which to confer resistance to most available antibiotics. The carbapenem antibiotics are usually reserved for the treatment of complicated or multidrug resistant (MDR) K. pneumoniae infections. The recent emergence of not only MDR but also pan-drug resistant (PDR) K. pneumoniae strains has signified that it is now more important than ever to understand the mechanisms by which these strains confer resistance so that we may find ways to combat or hinder this progression. This project aimed to investigate the regulation of the transcriptional activator RamA, its ability to confer a MDR phenotype, and the mechanisms employed by K. pneumoniae to confer levels of carbapenem resistance sufficient to result in therapy failure. The analysis of a panel of K. pneumoniae strains, containing both RamA expressers and non-expressers, demonstrated that the overexpression of RamA was sufficient to confer an MDR phenotype. Two compounds, chlorpromazine (CPZ) and tigecycline, were shown to act as inducers of ramA, romA and acrA transcription. CPZ exhibited synergy with the antibiotics chloramphenicol, norfloxacin and tetracycline, all of which are known substrates of the AcrAB efflux pump. The current lack of novel classes of antimicrobials in development indicate a potential for a compound, such as CPZ, to be developed and exploited for clinical use. The ability of both CPZ and tigecycline to cause mutations within ramR however, indicate that both compounds may have the ability to select for efflux mutants as a result of their ability to upregulate ramA, which in turn causes the upregulation of the AcrAB efflux pump. The regulation of RamA by the upstream gene ramR, which encodes a TetR family protein was investigated in K. pneumoniae isolates. Sequencing of the ramR genes revealed that strains exhibiting an MDR phenotype commonly contained mutations within their gene sequences. The complementation of a wildtype ramR into a strain containing a 32 amino acid deletion within its ramR, was shown to increase susceptibility to various antibiotics of different classes, and additionally downregulate the expression of ramA, romA and acrA. CPZ, ciprofloxacin and tigecycline K. pneumoniae mutants were shown to exhibit increased MICs to a broad spectrum of antibiotics with respect to their parent strains, and possess mutations within their ramR genes. Complementation of the wildtype ramR resulted in partial reversion to the parental phenotypes, indicating another mechanism must also be involved in conferring the MDR phenotypes. These studies indicated that RamR plays an important role as a negative regulator of RamA, but also that it is not the sole regulator. The development of reduced susceptibility to the carbapenems was investigated in two clinical strains of K. pneumoniae, K1 and K2, isolated from the urine of a single patient at different stages of antibiotic therapy. The strains were shown to exhibit similar resistance phenotypes with the exception of their susceptibilities to the carbapenems. PCR and phenotypic analyses revealed that neither strain contained any carbapenemases or AmpC enzymes, but both contained OXA-1, SHV-1 TEM-1 and CTX-M-15. Analysis of their OMP profiles indicated that both strains lacked OmpK35, and K2 additionally lacked OmpK36. Mutation studies showed that the phenotype and OMP profile exhibited by K2 could be achieved in K1 via single step mutations using ertapenem, imipenem or meropenem. Susceptibility testing of CTXM- 15 clinical strains showed that strains containing CTX-M-15 showed reduced activity against ertapenem in the presence of clavulanic acid. These studies indicated a potential role for CTX-M-15 in conferring reduced susceptibility to the carbapenems when found in conjunction with altered permeability and active efflux. The mechanisms of antibiotic resistance employed by K. pneumoniae are numerous and complex. This work highlights several of these mechanisms and, more importantly, how they can work in synergy with one another to devastating consequences.
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Davies, Claire Louise. "Multidrug resistance in bladder and breast cancer." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299289.
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Wishart, Gordon C. "Aspects of multidrug resistance in breast cancer." Thesis, University of Edinburgh, 1992. http://hdl.handle.net/1842/20307.
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The use of chemotherapy in the treatment of breast cancer is compounded by the development of clinical drug resistance in a large number of cases. One mechanism of resistance, multidrug (MDR), is associated with expression of a 170kDa transmembrane protein called P-glycoprotein (P-gp) which acts as an energy-dependent drug efflux pump. Although P-gp can be encoded by several MDR genes it is only expression of the mdr-1 gene which is associated with MDR in humans. P-gp has been identified in several human tissues and tumours but previous studies have failed to provide clear evidence of its presence in human breast cancer. Detection of P-gp, by immunohistochemistry using specific monoclonal antibodies, allowed confirmation of P-gp expression at low levels in the majority of 29 untreated, primary breast cancers suggesting a population of resistant cells was present even before exposure to cytotoxic drugs. Furthermore this expression was detected in stromal cells, as well as malignant cells, and this stromal cell immunostaining has been confirmed as mdr-1 expression by competitive inhibition using a specific blocking peptide. Examination of paired samples of normal breast and tumour from the same patient revealed P-gp expression only in ductal epithelial cells, but not stromal cells, of normal breast. Finally those patients whose tumours had the highest P-gp expression in malignant cells appeared to have a worse prognosis in terms of disease-free survival.
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Hoffman, Mary M. "Mechanism of MDR protein mediated multidrug resistance /." Access full-text from WCMC, 1997. http://proquest.umi.com/pqdweb?did=733008491&sid=6&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Ungvári, Johannes. "Synthese potentieller Modulatoren zur Überwindung der Multidrug Resistance." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=979642663.
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Lincoln, Maximilian Christian. "Multidrug resistance and collateral sensitivity of tumour cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0018/MQ37141.pdf.
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Romano, Pascale Renee. "Cell-specific expression of the multidrug resistance genes." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.339300.
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Holmes, Julie Ann. "Novel natural products as modifiers of multidrug resistance." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388321.
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Kamil, Wan Nur Ismah Binti Wan Ahmad. "Envelope permeability and multidrug resistance in Klebsiella pneumoniae." Thesis, University of Bristol, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.768194.
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Hewlett, Mark. "The evolution of resistance to multidrug antibiotic therapies." Thesis, University of Exeter, 2015. http://hdl.handle.net/10871/21596.
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The purpose of this thesis is to explore the interaction between antibiotics at sub-lethal doses, and E.coli. Initially we focussed on pairwise antibiotic interaction, and the potential to exploit these interactions to minimise antibiotic resistance. In testing the hypothesis that antagonism will slow adaptation by reducing selection for resistance we determined that there are conditions in which this fails to be the case. We furthermore caution against treating drug interactions as anything other than a dynamic property of the bacteria-drug interaction, by showing that the relationship between two drugs may be both synergistic and antagonistic depending on a variety of factors. Whilst exploring the adaptive response to drug combinations we discovered a highly unusual effect of Doxycycline to act as a growth stimulant to E.coli AG100. Chapter 3 and 4 are devoted to determining the nature and mechanism of this stimulation, and analysing any potential genomic changes using whole genome re-sequencing. Having shown that dose response is not always a monotone function of increasing drug dose, in chapter 5 we also look at the dose response in a diffusive context, using a custom built imaging system to show the common non-monotonicity of disk diffusion type assays, that manifest themselves as bullseye patterns of growth. We use a mathematical model to explore the ecological and adaptive reasons for such patterns. Finally in chapter 6 we look at the coevolutionary history of phage and E.coli REL606 strains, by determining trade-offs caused by lambda phage and the sole carbon source maltotriose both utilising the same porin (lamB) for cell entry.
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Zhang, Fang. "Regulation of multidrug resistance genes in mammary tumours." Thesis, University of Leicester, 1996. http://hdl.handle.net/2381/34282.
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Intrinsic or acquired multidrug resistance is a major impediment to the successful treatment of cancer by chemotherapy. One biochemical mechanism by which such multidrug resistance may develop is via the overexpression of the membrane transport protein P-glycoprotein (P-gp). P-gp is coded for by the multidrug resistance (mdr) genes that constitute a small conserved gene family. These genes are separated into two classes. Only the class 1 genes can confer a multidrug resistance phenotype, and are often over-expressed in a variety of tumours. Breast cancer is the highest incident cancer amongst women in western society, where, despite radical surgery, about 35% patients die from this disease due to a failure of chemotherapy. Although an association of P-gp expression with a poor prognosis has been shown in clinical studies, the mechanism which results in P-gp expression in breast cancer is not known. In vitro, cells selected for a multidrug resistance phenotype, by high concentration anticancer drugs, often have an mdr gene amplification and increased gene transcription rate. However, this does not appear to be a general mechanism of increasing mdr expression in tumours. To date, there have been no studies that have investigated regulation of mdr genes in an in vivo model of mammary tumourigenesis. In this study, differential expression of mdr genes and P-gp was characterised in chemical (N-methyl-N-nitrosourea) induced rat mammary tumours. It was found that expression of the class 1 genes (mdr1a and mdr1b) were consistently increased in the tumours, with the mdr1b gene being most highly induced. The expression of P-gp was located in a minority of neoplastic epithelial cells, often on the epithelial / stroma interface and surrounding necrotic areas. Single epithelial cells that had invaded the stroma also expressed P-gp, suggesting a possible association with invasive potential. Increased mdr1b gene expression in rat mammary tumours was due to an increased gene transcription rate measured by a RT-PCR based nuclear run-on assay. A specific mammary tumour nuclear factor (MTNF) was found to bind to the mdr1b promoter upstream of the transcription initiation site. It is likely that MTNF is responsible for increased the mdr1b gene transcription in rat mammary tumours. The relevance of this factor in human breast cancer need to be further investigated.
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Yiakouvaki, Anthie. "The link between multidrug resistance and oxidative stress." Thesis, University of Bath, 2003. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426177.
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Pajic, Marina Women's & Children's Health Faculty of Medicine UNSW. "The role of multidrug transporters in childhood malignancies." Awarded by:University of New South Wales. Women's & Children's Health, 2007. http://handle.unsw.edu.au/1959.4/41374.
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Multidrug resistance (MDR) is one of the foremost causes of treatment failure in childhood malignancies. MDR is a multifactorial process, but classic resistance to cytotoxic drugs has most often been associated with over-expression of one or more MDR transporter proteins in malignant cells, conferring on them the ability to extrude an extraordinarily diverse array of endo- and xenobiotics out of the cell. The best characterized multidrug transporters, P-glycoprotein (Pgp) and the Multidrug Resistance-associated Protein (MRP), belong to the ATP-binding cassette (ABC) gene superfamily, and have been previously implicated in the development of drug resistance in the clinical context. The work described herein examined the various aspects of the MDR genotype and phenotype in the childhood malignancies acute lymphoblastic leukaemia (ALL) and neuroblastoma. The first series of studies tested the hypothesis that morphine, a potential Pgp substrate, might influence the efficacy and/or toxicity of clinically used chemotherapy agents which are substrates for Pgp. The results, however, provided no evidence in a variety of human tumour cell lines of morphine influencing response to selected chemotherapeutic drugs. This finding is particularly important as morphine remains to be the opioid of choice for the treatment of cancer pain in the clinic. The second series of studies examined the effect of single nucleotide polymorphisms (SNPs) in the MDR1 gene, encoding Pgp, and in the MRP1 gene, on patient outcome in childhood ALL or neuroblastoma, with a view to identifying novel prognostic markers for these malignancies. It was found that two of the examined SNPs in the MRP1 gene were associated with improved outcome in neuroblastoma, which had not previously been demonstrated in this disease. Moreover, each of the relevant MRP1 SNPs were associated with lower MRP1 gene expression in both patient samples and tumour cell lines, supporting previous studies indicating that low MRP1 expression in neuroblastoma is strongly associated with improved patient outcome. Importantly, the results of this study suggest a role for selected MRP1 polymorphisms in predicting clinical response in neuroblastoma. Finally, a series of studies were undertaken, using both in vitro and in vivo model systems, to test the efficacy of putative small molecule inhibitors of the MRP1 gene and its transcriptional regulator, the MYCN oncogene, in neuroblastoma. These studies demonstrated for the first time the efficacy of a novel compound, 4H10, at reversing multidrug resistance either in cultured neuroblastoma cells, or in the MYCN transgenic mice, which develop neuroblastoma that closely mirror the human disease. The results indicate that inhibition of MRP1 function has potential clinical importance in the treatment of neuroblastoma, and therefore warrant further research in this area. In contrast, the results failed to provide evidence of the in vivo efficacy of the novel putative small molecule MYCN inhibitors analysed in these studies. Collectively, the findings of these studies contribute to a better understanding of the mechanisms of clinical drug resistance, and may help in the development of new approaches for risk assessment and treatment of aggressive childhood malignancies and thereby improve the long-term outlook of children diagnosed with these debilitating diseases.
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Wood, Daniel J. T. "Reversal of subcellular drug resistance mechanisms in multidrug resistant human KB carinoma cells." Thesis, University of York, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297167.
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Kioka, Noriyuki. "STUDIES ON THE MECHANISM OF ACQUIRING RESISTANCE BY HUMAN MULTIDRUG-RESISTANCE GENE MDR1." Kyoto University, 1991. http://hdl.handle.net/2433/78251.
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Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第4925号
農博第696号
新制||農||609(附属図書館)
学位論文||H3||N2389(農学部図書室)
UT51-91-X96
京都大学大学院農学研究科農芸化学専攻
(主査)教授 駒野 徹, 教授 大山 莞爾, 教授 佐々木 隆造
学位規則第4条第1項該当
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Ko, Wai-ting, and 高慧婷. "Molecular characterization of pyrazinamide resistance in Mycobacterium tuberculosis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193536.
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Tuberculosis (TB) is a highly infectious disease that causes the second highest mortality rate in human worldwide. The emergence of multi-drug resistance tuberculosis (MDR-TB) leads to a major public health problem in controlling TB-caused mortality. Pyrazinamide (PZA) is an important first-line drug in the treatment of MDR-TB. However, since the challenge in performing susceptibility test on PZA, World Health Organization has not published any data on the prevalence of PZA resistance in Mycobacterium tuberculosis (M. tuberculosis). Since the occurrence of PZA resistance makes MDR-TB more difficult to treat with poor prognosis, rapid detection method in PZA resistance is urgently needed. Since pncA mutation is highly associated with up to 98% PZA resistant M. tuberculosis strains, it is worthwhile to develop rapid molecular method for detecting PZA resistance. This study aims to identify the mutations in PZA resistant M. tuberculosis strains.
The first part of this study aims to characterize the pattern of pncA mutation among PZA-resistant and PZA-susceptible M. tuberculosis using Sanger sequencing method. Among all clinical isolates, 12 out of 29 cases of M. tuberculosis were resistant to PZA. All PZA-resistant M. tuberculosis strains harbored pncA mutation, whereas no known mutations were found among those PZA-susceptible strains, giving the positive predictive value to be 100%. Eight mutation patterns were found among 12 resistant isolates. Four of these pncA mutations have not been described previously by other studies. Study also characterizes the pattern of pncA mutation in 19 sputum specimens, with 2 mutation patterns found. Overall 10 mutation patterns were found in this study. Results show that the mutation of pncA gene is highly associated with PZA-resistant M. tuberculosis. Results also suggest the scattered and more extensive mutations in pncA gene that confer PZA resistance to M. tuberculosis.
The second and the last part of this study aims to evaluate the possibility of using molecular method to detect PZA resistance in routine clinical laboratory. Results show that using molecular sequencing to detect PZA resistance can shorten the turnaround time to about 3-4 working days. Since mutation of pncA was scattered along the entire pncA gene, using DNA sequencing approach may be the best strategy for the rapid detection of PZA resistance in M. tuberculosis.published_or_final_version
Medical Sciences
Master
Master of Medical Sciences
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Björkhem, Bergman Linda. "Thioredoxin reductase and selenium in carcinogenesis and multidrug resistance /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-954-4/.
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Ellis, Lucy C. J. "Human and rat multidrug resistance-associated proteins (MRP/Mrp)." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128325.
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The multidrug resistance associated proteins (MRP(human)Mrp (rat) are ATP-dependent transporters responsible for the efflux of a wide range of substrates, including endogenous compounds e.g. bilirubin, drug metabolites e.g. paracetamol glucuronide and fluorescent dyes e.g. 5 (and 6)-carboxy-2’,7’-dichlorofluorescein (CDF). Mrp1-6 (abccl-6) are expressed in rat liver, with Mrp2 being expressed at the highest level. Isolation of hepatocytes by in situ collagenase perfusion causes bile canalicular disruption and internalisation of Mrp2. Cells cultured in a sandwich configuration of Matrigel or collagen (Type 1) showed bile canalicular reformation at different days in cell culture, depending on the extracellular matrix and time of overlay. We have developed a method for quantifying Mrp-mediated efflux in hepatocytes cultured in a sandwich configuration of collagen (Type 1). This method is unique in its ability to distinguish between sinusoidal efflux, canalicular efflux and diffusion in intact hepatocytes. Alternative in vitro models of Mrp2-mediated efflux include the vesicular (direct and indirect methods) and the ATPase assays. We have used these assays to identify atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin as substrates of human and rat MRP2/Mrp2. A close correlation was seen between the kinetic parameters of transport of the Mrp2 substrate; CDF determined in sandwich cultured rat hepatocytes using the method above (Km = 3.5 – 9.9 μM), vesicle preparations (Km = 37.9 μM) and membrane preparations (Km = 18.7 μM). We also present data to implicate the nuclear receptors, PXR, CAR and FXR in the regulation of abcc2 and abcc3 and PXR and CAR in abcc1 gene regulation. Abcc2 and abcc5 are also up-regulated in response to a toxic insult to the cell, probably via Nrf2 activation, suggesting a role in cell defence.
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Tucker, Theodora. "Quantification of multidrug resistance transporters in human tissue samples." Thesis, University of Dundee, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.521691.
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De, Wet Heidi. "The nucleotide binding domains of multidrug resistance-p-glycoproteins." Doctoral thesis, University of Cape Town, 2001. http://hdl.handle.net/11427/2690.
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Fischer, Annett. "Role of multidrug resistance transporters in post-ischemic neuroprotection." kostenfrei, 2007. http://e-collection.ethbib.ethz.ch/view/eth:29997.
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Strauss, Bryan E. "Regulation of the human multidrug resistance gene by p53 /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9805803.
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PERINI, PIETRO. "Uptake/ efflux molecular mechanisms responsible for bosutinib multidrug resistance." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/29718.
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The multidrug resistance (MDR) has been identified in the 70s as a major cause of resistance to treatment with several unrelated agents. In the following 40 years MDR has been characterized in dept, and the molecular causes at the basis of this drug resistance are now largely known. The drug transporters play a central role in MDR, as the alteration of their expression levels is strictly related with MDR development. Down-regulation of uptake drug transporters and/or up-regulation of efflux drug transporters correlate with lower intracellular drug concentration, reduced activity on the target, and with resistance to treatment. The tyrosine kinase inhibitor (TKI) imatinib, currently the first line therapy for chronic myeloid leukemia (CML), showed MDR in presence of altered expression levels of OCT-1 (in patients), P-gp and BCRP (in vitro). The possible indication of OCT-1 levels as a prognostic factor for imatinib treatment is currently under debate. The hypothesis would be to increase the daily dose in patients with low expression levels of OCT-1.
The emerging therapeutic options for CML, mainly represented by new tyrosine kinase inhibitors nilotinib, dasatinib and bosutinib, offer a valid alternative in presence of imatinib MDR. Indeed, nilotinib and dasatinib show a different uptake/efflux pattern compared to imatinib, and it could be hypothesized that their efficacy could be unaffected by the drug transporters expression levels. The identification of drug transporters involved in new tyrosine kinase inhibitors is actually an active research field.
My PhD project focused on the identification of uptake/efflux mechanisms for a new TKI, bosutinib. First I produced cell lines overexpressing and overexpressing plus silencing the three main drug transporter. Then I evaluated the reliability of the cell models. Then I identified which transporter could be involved in bosutinib uptake/efflux, and finally I studied the biological and molecular relevance of the interaction between bosutinib and drug transporters.
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Xu, Zhiqiang. "Molecular analysis of staphylococcal multidrug transport protein QacA." Thesis, The University of Sydney, 2005. https://hdl.handle.net/2123/27983.
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The multidrug exporter QacA from Staphylococcus aureus confers resistance to a wide range of structurally-dissimilar monovalent and bivalent lipophilic, cationic compounds, including intercalating dyes, quaternary ammonium compounds (Qacs), diamidines, and biguanidines, many of which are used as antiseptics and disinfectants in current applications. To overcome such a problem, detailed understanding of the substrate-recognition and transport mechanisms of QacA is crucial. High-resolution structural studies of QacA can provide critical insights to these mechanisms. The
preliminary requirement of such studies is a regular supply of purified QacA protein in milligram quantities. In this study, an over-expression and purification system of QacA based on the E. coli expression vector pTTQ18His6 was established. Conditions for the over-expression and purification of the QacA protein were optimized, resulting in a
yield of approximately 600 pg of purified protein from 1 litre of bacterial culture. Circular dichroism (CD) spectroscopic analysis suggested that the purified QacA protein was structurally integral as demonstrated by its predominantly oc-helical structure, and substrate-binding assays were also performed.
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Cocker, Hilary Anne. "Drug resistance in paediatric rhabdomyosarcoma : pathways and circumvention." Thesis, Institute of Cancer Research (University Of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250655.
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Nastrucci, Candida. "Studies of P-glycoprotein and the chloride channel CIC-3." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249299.
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Gabriel, Mark. "Allostery : it's good to talk : (inter-domain communication in the multidrug transporter P-glycoprotein)." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249471.
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Pule, Caroline. "Defining the role of efflux pump inhibitors on anti-TB drugs in Rifampicin resistant clinical Mycobacterium Tuberculosis isolates." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/86758.
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Thesis (MScMedSc)--Stellenbosch University, 2014.ENGLISH ABSTRACT: Central dogma suggests that mutations in target genes is the primary cause of resistance to first and second-line anti-TB drugs in Mycobacterium tuberculosis. However, it was previously reported that approximately 5% of Rifampicin mono-resistant clinical M. tuberculosis did not harbor mutations in the rpoB gene. The present study hypothesized that active efflux plays a contributory role in the level of intrinsic resistance to different anti-TB drugs (Isoniazid, Ethionamide, Pyrazinamide, Ethambutol, Ofloxacin, Moxifloxacin, Ciprofloxacin, Streptomycin, Amikacin and Capreomycin in RIF mono-resistant clinical M. tuberculosis isolates with a rpoB531 (Ser-Leu) mutation. This study aimed to define the role of Efflux pump inhibitors (verapamil, carbonylcyanide m-chlorophenylhydrazone and reserpine) in enhancing the susceptibility to different anti-TB drugs in the RIF mono-resistant clinical isolates. The isolates were characterized by determining the level of intrinsic resistance to structurally related/unrelated anti-TB drugs; determining the effect of EPIs on the level of intrinsic resistance in the isolates and comparing the synergistic properties of the combination of EPIs and anti-TB drugs. To achieve this, genetic characterization was done by PCR and DNA sequencing. Phenotyping was done by the MGIT 960 system EpiCenter software to determine the MICs of the different anti-TB drugs and the effect of verapamil and carbonylcyanide m-chlorophenylhydrazone on determined MICs. Due to inability to test reserpine in a MGIT, a different technique (broth microdilution) was used for the reserpine experiment. Additionally; fractional inhibitory concentrations (FIC) indices were calculated for each of these drugs. The FIC assess the anti-TB drugs/inhibitor interactions. STATISTICA Software: version 11 was used for statistical analysis. Results revealed that the RIF mono-resistant isolates were sensitive at the critical concentrations of all 10 drugs tested, with the exception of Pyrazinamide. This could be explained by the technical challenges of phenotypic Pyrazinamide testing. A significant growth inhibitory effect was observed between the combination of EPI and anti-TB drug exposure in vitro. This suggests that verapamil, carbonylcyanide m-chlorophenylhydrazone and reserpine play a significant role in restoring the susceptibility (decrease in intrinsic resistance level) of the RIF mono-resistant isolates to all anti-TB drugs under investigation. Additionally, a synergistic effect was observed by the combination treatment of the anti-TB drugs with the different EPIs. Based on these findings, we proposed a model suggesting that efflux pumps are activated by the presence of anti-TB drugs. The activated pumps extrude multiple or specific anti-TB drugs out of the cell, this in turn decrease the intracellular drug concentration, thereby causing resistance to various anti-TB drugs. In contrast, the addition of EPIs inhibits efflux pump activity, leading to an increase in the intracellular drug concentration and ultimate cell death. This is the first study to investigate the effect of different efflux pumps inhibitors on the level of intrinsic resistance to a broad spectrum of anti-TB drugs in drug resistant M. tuberculosis clinical isolates from different genetic backgrounds. The findings are of clinical significance as the combination of treatment with EPI and anti-TB drugs or use of EPIs as adjunctives could improve MDR-TB therapy outcome.
AFRIKAANSE OPSOMMING: Sentrale dogma beweer dat mutasies in teiken gene die primêre oorsaak van die weerstandheid teen anti-TB-middels in Mycobacterium tuberculosis is. Vorige studies het getoon dat ongeveer 5% van Rifampisien enkelweerstandige kliniese M. tuberculosis isolate nie ‘n mutasie in die rpoB geen het nie. Die hipotese van die huidige studie was dat aktiewe pompe 'n bydraende rol speel in die vlak van intrinsieke weerstandheid teen 10 verskillende anti-TB-middels (Isoniasied, Ethionamied, Pyrazinamied, Ethambutol, Ofloxacin, Moxifloxacin, Siprofloksasien, Streptomisien, Amikasien and Capreomycin) in RIF enkelweerstandige kliniese M . tuberculosis isolate met 'n rpoB531 (Ser-Leu) mutasie. Die doel van hierdie studie was om die rol van uitpomp inhibeerders (verapamil, carbonylcyanide m-chlorophenylhydrazone en reserpien) te definieer in die verbetering van die werking vir verskillende anti-TB-middels in die RIF enkelweerstandige kliniese isolate. Die doelstellings van die studie was om die vlak van intrinsieke weerstandigheid teen struktureel verwante/onverwante anti-tuberkulose middels asook die effek van die EPIs op die vlak van intrinsieke weerstand in die isolate is bepaal. Verder is sinergistiese eienskappe van die kombinasie van EPIs en anti-TB-middels ondersoek. Hierdie doelstellings is bereik deur genetiese karakterisering deur PKR en DNS volgorde bepaling. Fenotipering is gedoen deur gebruik te maak van MGIT 960 EpiCenter sagteware om die Minimum Inhibisie Konsentrasie (MIC) van die verskillende anti-TB-middels en die effek van verapamil en carbonylcyanide m-chlorophenylhydrazone op die MIC te bepaal. Reserpien kan nie in die MGIT sisteem getoets word nie, and daarom is 'n ander tegniek (mikro-verdunning) is gebruik om die effek van reserpien te toets. Fraksionele inhiberende konsentrasies (FIC) is bereken vir elk van hierdie middels die anti-TB-middels / inhibeerder interaksies te bepaal. STATISTICA v11 sagteware is gebruik vir alle statistiese analises. Resultate van hierdie studie toon dat die RIF enkelweerstandige isolate sensitief is teen kritieke konsentrasies van al die middels, met die uitsondering van Pyrazinamied. Weerstandigheid van Pyrazinamied kan wees as gevolg van welbekende tegniese probleme met die standaard fenotipiese pyrazinamied toets. ‘n Beduidende groei inhiberende effek is waargeneem tussen die kombinasie van EPI en anti-TB middel blootstelling in vitro. Dit dui daarop dat verapamil, CCCP en reserpine 'n belangrike rol speel in die herstel van die sensitiwiteit (afname in intrinsieke weerstand vlak) van die RIF enkelweerstandige isolate aan alle anti-TB-middels wat ondersoek is. Daarbenewens is 'n sinergistiese effek waargeneem deur die kombinasie van die verskillende anti-TB-middels en die verskillende EPIs. Op grond van hierdie bevindinge het ons ‘n model voorgestel wat toon dat uitvloei pompe geaktiveer word deur die teenwoordigheid van anti-TB-middels en die geaktiveerde pompe dan verskeie of spesifieke anti-TB-middels uit die sel pomp. Dus verminder die intrasellulêre konsentrasie van die middel en veroorsaak daardeur weerstandigheid teen verskeie anti-TB-middels. Die byvoeging van EPIs inhibeer uitvloei pompe se werking en lei tot 'n toename in die intrasellulêre konsentrasie van die middels en uiteindelik die dood van die selle. Hierdie is die eerste studie wat die effek van verskillende uitvloei pompe inhibeerders op die vlak van intrinsieke weerstand teen 'n breë spektrum van anti-TB-middels in die middel-weerstandige kliniese isolate ondersoek. Die bevindinge kan van belangrike kliniese belang wees aangesien die kombinasie van behandeling met EPI en anti-TB-middels die uitkoms MDR-TB terapie kan verbeter.
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Abbaszadegan, Mohammad Reza. "Mechanisms of resistance to chemosensitizers in a multidrug resistant human multiple myeloma cell line." Diss., The University of Arizona, 1995. http://hdl.handle.net/10150/187140.
Full textAbstract:
Tumor cells in cancer patients acquire drug resistance as a result of chemotherapy. One type of acquired drug resistance is multidrug resistance (MDR) caused by the overexpression of P-glycoprotein, a transmembrane efflux protein. Inhibitors of P-glycoprotein or chemosensitizers such as verapamil are used to reverse MDR in cancer patients. Clinical studies have shown that some patients with P-glycoprotein positive cancer cells respond to the chemosensitizing effect of verapamil. However, this response is short lived and tumor cells become resistant to chemosensitizers. In order to study the mechanism of resistance to chemosensitizers, a human myeloma cell line, 8226/MDR₁₀V, was selected from a P-glycoprotein positive cell line, 8226/Dox₄₀, in the continuous presence of doxorubicin and verapamil. MDR₁₀V cells are consistently more resistant to MDR drugs than the parent cells, Dox₄₀. Chemosensitizers were less effective in reversing resistance in the MDR₁₀V compared to D0X₄₀ cells. Despite higher resistance to cytotoxic agents, MDR₁₀V expresses less P-glycoprotein in the plasma membrane compared to Dox₄₀. However, total cellular P-glycoprotein was the same in both cell lines suggesting a relocation of P-glycoprotein from plasma membrane into cytoplasm. Confocal immunofluorescence microscopy showed 2.5X more P-glycoprotein in the cytoplasm of MDR₁₀V cells as compared to D0X₄₀ cells. The relocation of P-glycoprotein was associated with a redistribution of doxorubicin. In D0X40 cells, doxorubicin was concentrated in the nucleus, whereas in MDR₁₀V cells, 90% of doxorubicin was found in the cytoplasm. We hypothesized that P-glycoprotein trafficking from the endoplasmic reticulum to the plasma membrane may be interrupted resulting in a higher concentration in the cytoplasm. To test this hypothesis, endoglycosidase H sensitivity of newly sensitized P-glycoprotein was examined. Medial Golgi processing of P-glycoprotein was identical between the two cell lines and the N-glycosylation of P-glycoprotein was complete by 3 hours. No mutations were found in MDR1 cDNA from MDR₁₀V cells compared to Dox₄₀ cells. These results suggest that increased resistance to cytotoxic drugs and chemosensitizers is associated with an altered intracellular location of P-glycoprotein which in turn causes a redistribution of doxorubicin.
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Ho, Yat-man Alex, and 何逸敏. "Molecular epidemiology of multidrug-resistant Acinetobacter baumannii." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197078.
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Acinetobacter baumannii is an important nosocomial pathogen worldwide because of its remarkable ability to acquire antibiotic resistance. The global emergences of multidrug-resistant A. baumannii (MDR-AB) clones are predominated by a number of widely disseminated clones, namely clonal complex (CC) 1, CC2, and CC3. In early 2010, we reported two major clones of MDR-AB, designated HKU1 and HKU2 belong to sequence types (ST) 96 and ST92, widely disseminating in our hospitals. ST92 is a predominant clone that is prevalent in more than 30 countries, whereas ST96 has been identified recently and is geographically confined to certain parts of China. Our previous study only investigated the isolates collected in the year 2005-2006. We therefore extended our investigation over a six-year period (2005-2010) to generate a more complete picture of the molecular epidemiology and resistance mechanisms in A. baumannii.
Firstly, we performed the susceptibility test on various antimicrobial agents and employed molecular methods to characterize the epidemiology of the target A. baumannii isolates. For the entire study period, increased resistance rates were noted for the seven antimicrobial agents, namely imipenem, piperacillin-tazobactam, cefoperazone, ticarcillin-clavulanate, ciprofloxacin, gentamicin and amikacin (P <0.01). Worryingly, an increased trend was also observed for the pandrug-resistant rate, from 0.2% in the year 2005-2006, to 1.9-2.9% in the year 2007-2008 and up to 6.0-8.1% in the year 2009-2010 (chi square for trend, P <0.001). Pulsed-field gel electrophoresis and multilocus sequence typing (PFGE/MLST) categorized 100 out of 108 (92.6%) isolates into four clones (PFGE/MLST), namely HKU2/ST92 (n = 14), HKU3/ST254 (n = 73), HKU4/ST137 (n = 5), and HKU5/ST362 (n = 8), respectively. PCR showed that 88.9% (96/108) of the amikacin-resistant isolates were armA positive and all isolates were found to harbour at least one of the OXA-type carbapenemases with frequencies as follows: OXA-51-like (98/108, 90.7%), OXA-23-like (85/108, 78.7%), OXA-58-like (9/108, 8.3%) and OXA-24-like (8/108, 7.4%).
Secondly, we compared the biological fitness of the circulating clones by performing the doubling time and adhesion experiment. The results demonstrated that HKU3/ST254 has a higher capability for replication and adherence to human bronchial epithelial cells. Together with the higher antibiotic resistance rate, the selective advantages in terms of biological fitness may facilitate the clonal expansion and wide dissemination of this lineage.
Finally, whole genome sequence data showed a high amount of resistance genes intermixed with various insertion sequence (IS) elements, integrons and transponsons clustering inside the resistance islands. The presence of a second genomic resistance island conferring aminoglycoside and sulphonamide resistance, additional loci outside the resistance islands harbouring resistance genes and the high amount of antibiotic efflux pumps in various A. baumannii genomes demonstrated that resistance islands contribute a significant part to the multidrug-resistant phenotype in A. baumannii but are not the only factor. The correlation analysis further demonstrated the significance of IS elements in the dissemination of antibiotic resistance genes in the A. baumannii genomes. As a whole, whole genome sequence data may provide an informative and efficient approach to generating a more comprehensive picture to study the resistance mechanism of the epidemic strains.published_or_final_version
Microbiology
Doctoral
Doctor of Philosophy
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Heaton, Victoria Josephine. "Molecular characterisation of etoposide resistance in human leukaemic cells." Thesis, St George's, University of London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299393.
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Masureel, Matthieu. "Molecular basis of secondary multidrug transport." Doctoral thesis, Universite Libre de Bruxelles, 2013. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209479.
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The Major Facilitator Superfamily groups a vast number of secondary transporters that import or export distinct substrates. Among these, multidrug antiporters constitute a peculiar class of transporters, both because of their multispecificity, recognizing structurally very diverse substrates, and because of their transport mechanism, that relies on bilayer-mediated extrusion of cytotoxic compounds. An accurate and detailed description of the conformational changes that underlie the transport cycle is still lacking and the structural basis for energetic coupling in these transporters has not been elucidated, with so far only limited crystallographic evidence available. We investigate the molecular basis of secondary multidrug transport with biochemical and biophysical studies on LmrP, a Major Facilitator Superfamily multidrug transporter from Lactococcus lactis. We used extensive continuous-wave electron paramagnetic resonance and double electron-electron resonance measurements on a library of spin-labeled LmrP mutants to uncover the conformational states involved in transport and to investigate how protons and ligands shift the equilibrium between conformers to enable transport. We find that the transporter switches between outward-open and outward-closed conformations depending on the protonation states of specific acidic residues forming a transmembrane protonation relay. We observe that substrate binding restricts the conformational freedom of LmrP and induces localized conformational changes. Our data allows to build a model of secondary multidrug transport wherein substrate binding initiates the transport cycle by opening the extracellular side to protons. Subsequent protonation of membrane-embedded acidic residues induces substrate release to the extracellular side and triggers a cascade of conformational changes that culminates in a proton release to the intracellular side. Parallel to this, we have optimized our purification and expression protocol in order to set up crystallization trials on LmrP. Through extensive screening and optimization of the lipidation state of LmrP, using ad hoc methods for sample preparation, we were able to obtain low-resolution diffracting crystals. By improving our lipidation technique and modifying the lipid composition we further improved crystal quality. Other factors such as ligand addition, the presence of secondary detergent and additives for controlling phase separation and nucleation were tested, paving the way to high resolution structure determination of LmrP.Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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Hercock, Carol Ann. "Function and dimerization of the human multidrug resistance pump : ABCG2." Thesis, University of Nottingham, 2011. http://etheses.nottingham.ac.uk/1920/.
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ABCG2 is a half-transporter that belongs to the G-subfamily of ABC (ATP- binding cassette) transporters, which are characterised by their unique domain organisation; an N-terminal nucleotide-binding domain (NBD) followed by a transmembrane domain (TMD) to its C-terminal. ABCG2 has been investigated as a multitask transporter widely distributed in normal tissues as well as overexpressed in cancer stem cells and cancer cell lines to confer protection against different xenobiotics and induce multidrug resistance (MDR), respectively. Since the time it was discovered, several studies investigated the effect of certain residues or subdomains within human ABCG2 affecting its substrate specificity, structure, function as well as its dimerization (or oligomerization) status. This study was designed to identify highly co-evolved residues within human cellular localization and/or function. The study also investigated ABCG2 dimerization via a recently developed tool; bimolecular fluorescence complementation (BiFC), through which visualisation of ABCG2 dimerization in live cells was enabled. According to co-evolutionary investigations, eight novel residues were chosen from a wide range of highly correlated coupled residues shared among ABCG- related sequences, and were used to design single mutants that were tested for ABCG2 expression, sub-cellular localization and function, besides control mutants of known effects. All variants were expressed at a comparable level to wild-type ABCG2R482 except for an I573A mutant that showed altered glycosylation level and enhanced intracellular retention. All mutants were functionally capable of extruding Pheophorbide A (PhA), Mitoxantrone and BODIPY-Prazosin, and inhibited by Fumitremorgin C (FTC), as revealed by fluorescent export studies and flow cytometry, except for two mutants, P485A and M549A, which showed altered inhibition profile with FTC. This study revealed that these two residues could participate in the inhibitor binding site or in the communication between the drug and inhibitor binding sites. Bimolecular fluorescence complementation analyses revealed that dimerization of N-terminally YFP-tagged ABCG2 constructs was specifically localized to the plasma membrane of live cells. However, mutating single residues, previously published to participate in ABCG2 dimer formation, did not significantly alter the BiFC signal. BiFC enabled the qualitative investigation of ABCG2 dimerization and function but was insensitive enough to map single residue changes within the dimer formation interface. This study opens the door for future investigations of conserved residues within human ABCG2 that could increase the depth of understanding allosteric interactions between drug and inhibitor binding sites within the transporter via applying a wider range of specific ABCG2 substrates and inhibitors. It also guides further studies to investigate the dimer formation status of ABCG2 and its possible inhibition to overcome multidrug resistance and failure of chemotherapy in cancer cells.
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Oluwatuyi, Moyosoluwa Olurele. "Natural product modulators of multidrug resistance (MDR) in Staphylococcus aureus." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406517.
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Neo, Soek Ying. "The role of multidrug resistance-associated protein in drug transport." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627326.
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Bagrij, Tatjana. "Studies of multidrug resistance-associated protein function in lung cells." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621764.
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Księżopolska, Ewa 1987. "Genomic changes driving the acquisition of multidrug resistance in Candida glabrata." Doctoral thesis, TDX (Tesis Doctorals en Xarxa), 2021. http://hdl.handle.net/10803/672386.
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This project was set out to broaden our knowledge of the processes driving the emergence of antifungal drug resistance in an opportunistic yeast pathogen Candida glabrata. More precisely, we sought to find the mutational signatures of drug resistance and cross-resistance to representatives of two clinically important antifungal drug classes, azoles and echinocandins. By combining in vitro evolution with phenotypic screening and comparative genomics analysis we investigated the relationship between genomic changes, fitness and drug susceptibility to shed light on the cellular mechanisms and evolutionary constraints of antifungal drug resistance in this important pathogen
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Seebacher, Nicole Aveline. "Overcoming the Dual Mechanism of Stress-Induced, Pgp-Mediated Drug Resistance using Novel Thiosemicarbazones." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13847.
Full textAbstract:
Multi-drug resistance (MDR) is the principal mechanism by which many cancers develop resistance to chemotherapy drugs. It is the major factor responsible for the failure of many forms of chemotherapy. P-glycoprotein (Pgp) is the most highly studied ABC transporter involved in the efflux of cytotoxic substances out of the cell. Studies have shown that Pgp expression is up-regulated in tumour cells through the activation of the hypoxia-inducible factor-1 (HIF-1) pathway. Interestingly, this protein is typically up-regulated by conditions of oxidative stress, such as hypoxia and nutrient limitation, and has been measured at elevated levels within tumours. Consequently, the tumour micro-environment may play an important part in regulating MDR. For the first time, the work reported in this thesis reveals underlying cellular pathways involving regulation of both surface and intracellular MDR by the tumour micro-environment. Moreover, the use of novel thiosemicarbazones to overcome MDR is demonstrated as a promising therapeutic strategy in combination with common chemotherapeutic agents that are subject to lysosomal trapping. These findings may help significantly improve the activity of existing chemotherapeutics and help improve patient treatment outcomes with potent thiosemicarbazones, such as Di-2-pyridylketone 4-cyclohexyl, 4-methyl-3-thiosemicarbazone (DpC), that will enter clinical trials in late 2015.
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Stein, Ulrike Susanne. "Multidrug Resistenz in Tumorzellen." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2003. http://dx.doi.org/10.18452/13871.
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Multidrug Resistenz (MDR), die simultane Resistenz gegenüber strukturell und funktionell nicht-verwandten Zytostatika, stellt eine wesentliche Ursache für unzureichende Behandlungserfolge maligner Erkrankungen dar. Die inherente Resistenz bzw. Resistenzentwicklung gegenüber chemotherapeutischen Substanzen ist vor allem die Folge der Präsens und Regulation unterschiedlicher Transportproteine wie MDR1, MRP1, BCRP und MVP. In der Konsequenz kommt es zu alteriertem Influx und/oder Efflux von Zytostatika, verminderter Akkumulation und Effektivität von Chemotherapeutika. Sowohl Zytostatika als auch Zytokine zeigten modulierende Einflüsse auf die Expression der MDR-Gene MDR1, MRP1 und MVP (Kapitel 2-9). Zytostatika wie Adriamycin resultierten vorwiegend in induzierten MDR1-Expressionen, dem hauptsächlichen Interventionstarget zur Überwindung des klassischen MDR-Phänotyps. Zytokine wie TNFa führten, extern appliziert als auch durch Gentransfer, zur Chemosensitivierung der Tumorzellen, verbunden mit Down-Regulationen von MDR1 und MVP. Die Zytokin-vermittelte Überwindung des klassischen MDR-Phänotyps weist auf die Inklusion definierter Zytokine in etablierte Chemotherapieprotokolle hin, wie bereits angewendet bei der hyperthermen isolierten Extremitätenperfusion mit TNFa (Kapitel 13). Die Verwendung BCRP-spezifischer Ribozyme demonstrierte deren Potential zur Überwindung des BCRP-bedingten, atypischen MDR-Phänotyps. Darüber hinaus wurde gezeigt, dass die Expression der ABC-Transporter als auch des MVP durch Hyperthermie temperatur- und zeitabhängig induzierbar ist (Kapitel 10-13). Diese Hyperthermie-Induktion wird für MDR1 und MRP1 über den Transkriptionsfaktor YB-1 zeitnah zum Stressereignis vermittelt. In der klinischen Situation konnte anhand verfügbarer Biopsien von Kolonkarzinomen, Sarkomen und Melanomen, jeweils mittels Hyperthermie im Kontext multimodaler Behandlungsregime behandelt, kein direktes, generelles Risiko einer MDR1- oder MRP1-vermittelten, Hyperthermie-bedingten Induktion/Verstärkung einer MDR beobachtet werden. Die Analyse der Promotoren MDR-assoziierter Gene wie MDR1 und MVP zeigte deren Induzierbarkeit durch unterschiedliche Therapie-relevante Faktoren wie Zytostatika und Hyperthermie in verschiedenen in vitro- und in vivo-Modellen (Kapitel 10,14-20). Spezifische Sequenzmotive sind für die Stressfaktor-induzierte Bindung von Transkriptionsfaktoren wie YB-1 verantwortlich; Mutationen in diesen Sequenzbereichen modulierten die Induzierbarkeit (Kapitel 14,15,20). Der Einsatz Therapie-induzierbarer Promotoren unterschiedlicher MDR-Gene wie MDR1 (Kapitel 14-18) und MVP (Kapitel 19,20) erlaubt somit generell die Anpassung an etablierte Behandlungsprotokolle verschiedener Tumorentitäten. In fortführenden Arbeiten bleibt die erfolgreiche Anwendung von Therapie-induzierbaren MDR-Promotorsequenzen zur Expression therapeutisch relevanter Gene im Kontext einer Gentherapie maligner Erkrankungen zu prüfen.Multidrug resistance, the simultaneous resistance towards structurally and functionally unrelated cytostatic drugs, still represents a major cause of cancer treatment failure. Inherent or acquired resistance against a wide variety of chemotherapeutic drugs depends mainly on the presence and regulation of different transporter proteins, such as MDR1, MRP1, BCRP, and MVP. Thus, decreased uptake and/or increased efflux, lowered net accumulation, and in consequence, less efficiency of anti-cancer drugs is the clinical hurdle to struggle with. Cytostatics as well as cytokines showed modulating effects on the expression of the MDR-associated genes MDR1, MRP1, and MVP (chapter 2-9). Cytostatics such as adriamycin resulted mainly in increased expression of the MDR1 gene, the most prominent intervention target for the reversal of the classical MDR phenotype. Cytokines such as TNFa, externally applied or by gene transfer, led to chemosensitization of tumor cells, and to down regulation of MDR1 and MVP. This cytokine-mediated reversal of the classical MDR phenoype refer to the inclusion of defined cytokines into established chemotherapy protocols, as already realized by the hyperthermic isolated limb perfusion with TNFa (chapter 13). The employment of BCRP-specific ribozymes demonstrated their potential to reverse the BCRP-mediated atypical MDR phenotype. Furthermore it was shown, that the expression of the ABC transporters as well as of MVP was inducible by hyperthermia in a temperature and time-dependet manner (chapter 10-13). This hyperthermia-caused induction of MDR1 and MRP1 is mediated by the transcription factor YB-1 timely close to the stress event. However, no direct, general risk of a MDR1- or MRP1-mediated hyperthermia-caused induction/enhancement of the MDR phenotype was observed in clinical settings, analyzed by using biopsies available from colon carcinomas, sarcomas, and melanomas, which were treated with hyperthermia in the context of multimodal regimes. The analyses of promoters of the MDR-associated genes MDR1 and MVP revealed their inducibility by different therapy-related factors such as cytostatics and hyperthermia in several in vitro- and in vivo models (chapter 10,14-20). Specific sequence motifs were found to be responsible for the stress-induced binding of transcription factors; mutations within these sequence regions modulated their inducibility (chapter 14,15,20). Thus, the employment of therapy-inducible promoters of different MDR genes such as MDR1 (chapter 14-18) and MVP (chapter 19,20) allows the improvement of established treatment protocols for different tumor localizations. Based on this, the succesful use of therapy-inducible MDR promoter sequences for the expression of therapeutically relevant genes in the context of a gene therapy of cancer represents an ambitious goal for the future.
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Vlerken, Lilian Emilia van. "Modulation of multidrug resistance in cancer using polymer-blend nanoparticles : thesis /." Diss., View dissertation online, 2008. http://hdl.handle.net/2047/d10017355.
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Chuanchuen, Rungtip. "Studies on multidrug efflux systems and triclosan resistance in Pseudomonas aeruginosa." Access citation, abstract and download form; downloadable file 8.57 Mb, 2004. http://wwwlib.umi.com/dissertations/fullcit/3131663.
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Manciu, Liliana. "Structural characterization of intermediate states occuring during chemotherapeutic agents transport mediated by Multidrug resistance protein 1 (MRP1), a protein involved in multidrug resistance of cancer cells." Doctoral thesis, Universite Libre de Bruxelles, 2003. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211217.
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