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首页> 外文学位 >Characterization of D-boroAla as a novel broad-spectrum antibacterial agent targeting D-Ala-D-Ala ligase & designer linkers: Model reactions and linear free energy relationships in the reactivitiy and design of solid-phase linkers.
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Characterization of D-boroAla as a novel broad-spectrum antibacterial agent targeting D-Ala-D-Ala ligase & designer linkers: Model reactions and linear free energy relationships in the reactivitiy and design of solid-phase linkers.

机译：D-boroAla作为靶向D-Ala-D-Ala连接酶和设计器接头的新型广谱抗菌剂的表征：固相接头的活化和设计中的模型反应和线性自由能关系。

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摘要

Bacterial infections were the major cause of death and morbidity prior to the development of modern antibiotics, and the increasing resistance of pathogenic bacteria to commonly used antibacterial agents is a major public health concern. During our efforts to develop transition-state analog inhibitors for bacterial cell wall-synthesizing enzymes, we observed that D-boroAlanine (D-Ala with the -COOH group replaced with a -B(OH)2 group) had effective antibacterial activity. In the first part of this dissertation, we describe the antibacterial properties of D-boroAla, structure-activity correlation among several D-boroAla homologs, and determination of the biochemical mechanism for D-boroAla's antibacterial activity. This study demonstrates that D-boroAla has broad-spectrum antibacterial activity and targets D-Ala-D-Ala ligase (DDL) in the alanine branch of bacterial cell wall biosynthesis.;Vancomycin exerts its antibacterial effect by binding to the D-Ala-D-Ala termini of pentapeptide peptidoglycan precursors, thereby interfering with the last steps of bacterial cell wall biosynthesis. In the most clinically common resistance mechanisms in VRE, the terminal D-Ala-D-Ala moiety of peptidoglycan precursors is replaced by D-Ala-D-Lac. The middle section of the dissertation deals with developing an LC-MS/MS assay for detection and quantitation of D-Ala-D-Lac, the key intermediate for most types of vancomycin resistance. This assay was validated and then used to demonstrate the effect of vancomycin induction on alanine branch metabolites---including D-Ala-D-Lac, in VRE.;Considerable research has been done on the synthesis of peptides and peptide mimetics using classical solid-phase peptide synthesis (SPPS) in the classical C-to-N direction. However, this strategy is not generally useful for preparing C-terminally modified peptide derivatives, which are of high interest as bioactive agents and drugs. SPPS in the N-to-C direction inverse SPPS (ISPPS) would provide the synthetically versatile C-terminal carboxyl group for further elaboration. Prior studies in our laboratory established the feasibility of performing ISPPS using readily available amino acid OtBu esters. In the last section of this dissertation, described efforts to develop a backbone amide attachment linkers with the appropriate chemical stability for ISPPS i.e. stable to 25% TFA/DCM treatment and cleavable with 5% HBr/TFA. Candidate linkers were then loaded onto aminomythylated polystyrene resin to demonstrate an effective method for ISPPS using amino acid t-butyl esters. Chemical sensitivity to different capping groups on sensitivity to cleavage was demonstrated and several tripeptides were synthesized using this approach.
机译：在现代抗生素出现之前，细菌感染是导致死亡和发病的主要原因，而致病细菌对常用抗菌剂的耐药性增加是主要的公共卫生问题。在我们努力开发细菌细胞壁合成酶的过渡态类似物抑制剂的过程中，我们观察到D-boroAlanine（D-Ala的-COOH基团被-B（OH）2基团取代）具有有效的抗菌活性。在本文的第一部分，我们描述了D-boroAla的抗菌特性，几种D-boroAla同系物之间的结构-活性相关性，以及对D-boroAla抗菌活性的生化机制的确定。这项研究表明D-boroAla具有广谱抗菌活性，并在细菌细胞壁生物合成的丙氨酸分支中靶向D-Ala-D-Ala连接酶（DDL）;万古霉素通过结合D-Ala-发挥其抗菌作用五肽肽聚糖前体的D-Ala末端，从而干扰细菌细胞壁生物合成的最后步骤。在VRE中临床上最常见的耐药机制中，肽聚糖前体的末端D-Ala-D-Ala部分被D-Ala-D-Lac取代。论文的中间部分涉及开发用于检测和定量D-Ala-D-Lac的LC-MS / MS分析方法，D-Ala-D-Lac是大多数万古霉素耐药性的关键中间体。该测定方法经过验证，然后用于证明VRE中万古霉素诱导对丙氨酸分支代谢产物-包括D-Ala-D-Lac的影响;在使用经典固体合成肽和肽模拟物方面已经进行了相当多的研究经典C到N方向的反相肽合成（SPPS）。然而，该策略通常不适用于制备作为生物活性剂和药物而备受关注的C-末端修饰的肽衍生物。在N到C方向上的SPPS逆SPPS（ISPPS）将提供合成通用的C末端羧基，以供进一步阐述。我们实验室的先前研究确定了使用容易获得的氨基酸OtBu酯进行ISPPS的可行性。在本论文的最后一部分中，描述了开发具有对ISPPS合适的化学稳定性，即对25％TFA / DCM处理稳定并可用5％HBr / TFA裂解的骨架酰胺连接接头的努力。然后将候选连接基加载到氨基甲酰化聚苯乙烯树脂上，以证明使用氨基酸叔丁酯进行ISPPS的有效方法。证明了对不同封端基团的化学敏感性对裂解的敏感性，并使用这种方法合成了一些三肽。

著录项

  • 作者

    Putty, Sandeep.;

  • 作者单位

    University of Missouri - Kansas City.;

  • 授予单位 University of Missouri - Kansas City.;
  • 学科 Health Sciences Pharmacy.;Chemistry Analytical.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 228 p.
  • 总页数 228
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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