Stuttgart, Univ., Diss., 2002.

Stuttgart, Univ., Diss., 2005.

Thesis (doctoral)--Lund University, 1998. / Thesis statement on t.p. verso. Includes bibliographical references.

Thesis (Ph. D.)--Miami University, Dept. of Chemistry and Biochemistry, 2004. / Title from second page of PDF document. Includes bibliographical references.

Class of 2017 Abstract / Objectives: The objective of this retrospective cohort chart review was to evaluate the safety and efficacy of extended infusion beta-lactam regimens as part of treatment of acute CF pulmonary exacerbations in adults and pediatric patients. Methods: Inclusion criteria: adult and pediatric patients (age 1 month or older) with CF diagnosis who were admitted to BUMC-T for acute pulmonary CF exacerbation, and who received meropenem, imipenem, aztreonam, piperacillin-tazobactam, and or cefepime during their hospitalization (between 1/1/2011 and 10/30/2015). Exclusion criteria: pregnant women and admissions less than 24 hours. The two groups evaluated were patients receiving treatment (group 1) prior to extend infusion practices (Jan 2011 – Dec 2012) and (group 2) after implementation of extend infusion practices (Jan 2013 – Oct 2015). Data was collected from medical records using both the Sunrise Clinical Manager and EPIC electronic medical record systems. The data was then analyzed for differences in efficacy outcomes (e.g., length of hospitalization, lung function, return to baseline lung function), changes in renal and hepatic function, incidence of documented adverse drug effects, and potential factors associated with increased risk for changes in renal or hepatic function with use of extended infusion beta‐lactam regimens. Results: Pending. Efficacy outcomes: - length of hospitalization - improvement in lung function - return to baseline lung function Safety outcomes: - changes in renal and hepatic function - incidence of documented adverse drug effects - potential factors associated with increased risk for changes in renal or hepatic function Conclusions: Pending. As this study is being conducted at one academic medical center, conclusions may not be generalizable to other institutions.

Polyketides are a class of natural products that exhibit remarkable structural and functionally diversity and are highly sought after due to their medicinally important activities. For many decades now, polyketide synthases (PKSs), the mega-enzymes responsible for biosynthesis of polyketides have been the focus of extensive investigation to make new polyketides by polyketide engineering strategies. While there are many established methods to investigate polyketide enzymes and biosynthesis mechanisms, they have substantial shortcomings that have limited the extent of success with polyketide engineering efforts. This thesis focuses on developing simple, flexible yet powerful tools for examining polyketide biosynthesis by overcoming some deficiencies in currently used techniques. Reactive heterocylces have been designed for direct labeling of key polyketide synthase enzymes to provide a direct insight into its functions and mechanisms. First β-lactones and then β-lactams have been used as small molecule probes to perform site-specific labeling of acyl carrier proteins and further used for mechanistic interrogation of key steps in polyketide biosynthesis. The utility of these probes has been demonstrated by comparison to traditional probes and has been successfully applied to examine substrate selectivity of keto synthases, key enzymes in polyketide biosynthesis. The applications of the tools described in this manuscript only scratch the surface of their capabilities and are expected to significantly aid in the study of new and existing PKS systems leading to improved understanding of how these extraordinary biosynthetic machines function.

No description available.

The increasing incidence of Mycobacterium abscessus (Mab) infections is a global concern as the treatment failure rate is more than 50%. Mab is an opportunistic pathogen, thriving in harsh conditions in the environment and in hosts. To respond to these conditions, Mab employs many signal transduction mechanisms. This work characterizes two non-redundant systems using a novel mechanism in Mab: BlaRI-type protease-mediated two-component systems. In the Staphylococcus aureus prototype, BlaR binds β-lactams with a C-terminal extracellular sensing domain, activating BlaR through acylation and autoproteolysis. Activated BlaR then cleaves DNA-bound dimerized BlaI, disrupting repression by BlaI and enabling transcription of blaZ, a β-lactamase. Before this work, the only characterized mycobacterial BlaRI ortholog was in Mycobacterium tuberculosis. Based on sequence homology, three possible BlaRI homologs were identified in Mab, and two of these systems are characterized in this work. After comparing structural models to BlaRSa and BlaIMtb, MAB_2414c-2415c (BlaIR1Mab) and MAB_4287-4288 (BlaIR2Mab) were established as BlaRI systems in Mab. While BlaRI systems typically regulate β-lactam resistance, neither BlaIR1Mab nor BlaIR2Mab mediate a response to β-lactams, consistent with their lack of an extracellular sensing domain. Instead, both BlaIR1Mab and BlaIR2Mab appear to control regulons comprised of genes related to respiration and redox homeostasis and respond to the respiration inhibitor clofazimine (CFZ) by de-repressing their respective regulons. Despite sharing this cue, BlaIR1Mab and BlaIR2Mab have distinct regulons with some potential overlap and do not appear capable of binding the motif of the other system. The regulation of respiration and energy metabolism but not antibiotic resistance by BlaRI systems is unique to Mab, and the role of the unprecedented third system remains to be investigated. Elucidation of the full regulons and roles of the three Mab BlaIR systems and mechanisms of signal transduction will undoubtedly reveal novel aspects of Mab-host interactions.

The synthesis of p-lactams has been of foremost importance since the discovery of penicillin by Sir Alexander Fleming, in 1928, and its susequent structure elucidation in 1945. Ethyl N-2-bromo-alkylcarbamates show considerable potential as precursors to p- lactams. In the past, p-lactams have been prepared by many methods, none of which have involved 2-3 bond formation. The proposed ring closure using ethyl N-2-bromoalkylcarbamate involves 2-3 bond formation, making this method of synthesis novel. This work describes two attempted methods of cyclisation. The first using a Grignard reagent, and the second, using abstraction of an acidic proton a to a phosphonate group. These methods of intramolecular cyclisation were based on analogous intermolecular additions, which are also described. The second method was also used to determine the general potential of ethyl N-bromo- alkylcarbamtes as precursors to other heterocyclic systems. / Thesis (M.Sc.)-University of Natal, Durban, 2001. / NRF & NRF/DEA & T.

The employment of enzymes and whole cells has been important in many industries for centuries. However, it is only in the last 30 years that the use of enzymes for the synthesis of high-value fine chemicals has enjoyed increasing popularity. In fact, esterases and lipases are used almost routinely these days to provide optically active building blocks for the construction of imaginative new routes to chiral target molecules. The major topic of this work describes the utilization of enzymes (namely lipases) in the synthesis and modification of natural and non-natural compounds. Chapter 1 outlines the strengths and weaknesses of the most widely used enzyme systems and a description of a brief summary on the state of the art of biotransformations with special emphasis on the general applicability and reliability of various reaction types is described. Chapter 2 describes the enzymatic resolution of various 3-acetoxy-4-aryl-substituted azetidin-2-ones. Following screening of enzymes, such as Novozym-435, PS-30, PPL and AYS the best conditions were a phosphate buffer with PS-30 as the enzyme. The resulting products were the (3S, 4R)-3-hydroxy-4-aryl-substituted azetidin-2-ones and the unreacted (3R, 4S)-3-acetoxy-4-aryl-substituted azetidin-2-ones. Reactions generally occurred with high conversion and high selectivity. In Chapter 3, the regioselective transesterifications and hydrolysis of peracylated sophorolipid (SL) derivatives catalyzed by lipases was investigated. It was confirmed from the detailed spectral analysis of the products that transesterification failed to furnish any free hydroxyls on the sophorose ring. Instead, transesterification took place on the methyl ester located at the carboxylic end of the 17-hydroxyoctadecenoic acid chain attached to the C-1' position of the sophorose ring. In Chapter 4, the chemo-enzymatic syntheses of enantiomerically pure R and S imperanene from vanillin are described. The key step entails the asymmetrization of a prochiral diol using lipase PS-30. The resulting monoacetate has enantiomeric excesses of >97%. Biocatalysts represent a new class of chiral catalysts useful for a broad range of selective organic transformations. It is stating the obvious to say that biocatalysis is not a panacea for synthetic organic chemistry. However, advances over the past thirty years mean that it would be a serious mistake not to consider the employment of a biocatalyst, in, perhaps, the key step in a sequence of transformations that turn a cheap starting material into an expensive fine chemical.