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首页> 外文学位 >Wall teichoic acid biosynthesis as a novel antimicrobial target in Staphylococcus aureus.
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Wall teichoic acid biosynthesis as a novel antimicrobial target in Staphylococcus aureus.

机译：壁板壁酸生物合成作为金黄色葡萄球菌中的新型抗菌靶标。

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摘要

Antibiotic resistance poses a major threat to human health, and invasive methicillin resistant Staphylococcus aureus (MRSA) infections have emerged as a leading cause of life-threatening infections in the United States. MRSA infections already cause more deaths each year in the U.S. than HIV/AIDS (∼20,000 in 2005), and the mortality rate is expected to increase. Resistance has recently appeared to vancomycin, linezolid, and cubucin antibiotics used for the treatment of MRSA infections. These facts underscore the ongoing need for novel compounds and strategies to combat S. aureus infections. The content of this thesis pertains to evaluating a new strategy to treat S. aureus infections by targeting Wall Teichoic Acid (WTA) biosynthesis.;Chapter One provides an introduction into the areas of antibiotic discovery and resistance as well as background information regarding the WTA biosynthesis field of research.;In Chapter Two, the WTA biosynthetic pathway for S. aureus is described. Using a series of genetic and biochemical experiments, we propose and validate a new pathway for S. aureus WTA biosynthesis. Through this work we were able to identify which gene products within the pathway serve as either antivirulence or antibiotic targets. This understanding of the WTA biosynthetic pathway in S. aureus is crucial for the development of this pathway as an antimicrobial target.;Chapter Three discusses the discovery of a small molecule inhibitor, targeting WTA biosynthesis, known as targocil. Targocil is the first reported antibiotic that functions by inhibiting WTA biosynthesis, a long sought after antimicrobial target, and it utilizes a novel mechanism of resistance. Since the pathway is not essential for survival, the easiest route to resistance is to shut off WTA biosynthesis. However, WTA expression is critical for host colonization and infection, and we have shown that targocil escape mutants are attenuated in their pathogenicity.;The work described in these Chapters lays the foundation for determining whether targeting WTA biosynthesis is efficacious in treating S. aureus infections. The hope for this work is to provide lead compounds that will be successful at combating bacterial resistance.
机译：抗生素耐药性对人类健康构成重大威胁，在美国，侵袭性耐甲氧西林的金黄色葡萄球菌（MRSA）感染已成为威胁生命的感染的主要原因。在美国，MRSA感染导致的死亡人数每年超过艾滋病毒/艾滋病（2005年约为20,000），并且死亡率有望提高。最近出现了对用于治疗MRSA感染的万古霉素，利奈唑胺和cubucin抗生素的耐药性。这些事实强调了对抗新型金黄色葡萄球菌感染的新型化合物和策略的持续需求。本论文的内容涉及通过靶向壁破壁酸（WTA）生物合成来评估治疗金黄色葡萄球菌感染的新策略。第一章介绍了抗生素的发现和耐药性领域以及有关WTA生物合成的背景信息第二章介绍了金黄色葡萄球菌的WTA生物合成途径。通过一系列的遗传和生化实验，我们提出并验证了金黄色葡萄球菌WTA生物合成的新途径。通过这项工作，我们能够确定途径中的哪些基因产物可作为抗病毒或抗生素靶标。对金黄色葡萄球菌中WTA生物合成途径的这种了解对于该途径作为抗微生物靶标的发展至关重要。第三章讨论了一种针对WTA生物合成的小分子抑制剂，即targocil。 Targocil是第一个报道的通过抑制WTA生物合成起作用的抗生素，WTA生物合成是长期以来追求的抗菌目标，并且它利用了新型的耐药机制。由于该途径对于生存不是必需的，因此抵抗的最简单途径是关闭WTA生物合成。然而，WTA的表达对于宿主定植和感染至关重要，并且我们已经表明，targocil逃逸突变体的致病性减弱。；这些章节中描述的工作为确定靶向WTA生物合成对于治疗金黄色葡萄球菌感染是否有效奠定了基础。 。这项工作的希望是提供能够成功对抗细菌耐药性的先导化合物。

著录项

  • 作者

    Swoboda, Jonathan Guyon.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 100 p.
  • 总页数 100
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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