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京都大学 / 新制・課程博士 / 博士(医学) / 甲第24090号 / 医博第4866号 / 新制||医||1059(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 岩田 想, 教授 林 康紀, 教授 松田 道行 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Concomitant with antibiotic use is the development of bacterial strains that are resistant to such compounds. Presently, the rate at which antibiotic-resistant pathogenic bacteria are emerging is outpacing our resupply of new antibacterials; therefore, renewed efforts to identify novel therapies are urgently needed. Transition metals are required by all life forms and, for bacteria, an adequate supply of nutrient metal is necessary to establish infection in a host. Indeed, as an antibacterial defense mechanism, eukaryotes have developed various means by which to restrict the availability of metal to the invading pathogen, thereby limiting its chances for successful colonization. As such, bacterial metal acquisition and homeostasis have been suggested as potential antibiotic targets to explore for the identification of new antibacterial small molecules. In this thesis I discuss my development of a high-throughput screening assay that specifically selects for compounds that perturb bacterial iron homeostasis. The results of this work led to the identification of a series of spiro-indoline-thiadiazole compounds that are toxic to bacteria via iron chelation. In addition to molecules that perturb the availability of bacterial intracellular iron, we present a series of spiro-indoline-thiadiazole analogs that inhibit bacterial growth by limiting zinc availability. Furthermore, we show that the respective zinc-perturbing analogs re-sensitize an otherwise drug-resistant strain of NDM-1-harbouring Klebsiella pneumoniae to carbapenem antibiotics. We discuss the potential for this class of compounds to serve as carbapenem adjuvants for treating infections caused by metallo-β-lactamase-containing pathogens. / Thesis / Doctor of Philosophy (PhD)

The thesis begins by examining the history of the newborn screening (NBS) process in the United States and why it is the way it is today. The next section explores why certain genetic conditions, such as Long QT Syndrome (LQTS), do not fulfill requirements for the recommended uniform screening panel (RUSP). Lastly, ethical considerations of expanded NBS in the age of genomic technology are examined by highlighting the principles of autonomy, beneficence, equity, cost-effectiveness, privacy and trust. Overall, the NBS process benefits children by identifying serious rare diseases and intervening early to prevent harm; however, a deeper ethical analysis highlights some of the concerns with expanding mandatory, universal NBS in the age of precision medicine. The focus must be on educating the public and healthcare professionals about the NBS process and using evidence-based protocols for adding new conditions to the panel. / Urban Bioethics