A common denominator of pathogenesis; a rare opportunity for novel therapeutic de

描述（由申请人提供） 翻译后摘要：20世纪世纪见证了医学的几个重大进展。也许最重要的是发现了细菌感染的抗生素和几种主要病毒的有效疫苗。不幸的是，针对细菌的有效疫苗的开发落后于类似的抗病毒策略。再加上抗生素耐药性的上升和制药业对寻求新型抗生素缺乏兴趣，我们有可能失去与细菌病原体的斗争。本文描述了利用细菌毒素作为抗菌剂的新靶标和疫苗开发的抗原的非常规策略。 为了明智地解决细菌病原体带来的日益严重的威胁，需要做出更多努力来揭示毒力的分子基础。我们的研究小组专门从事生物信息学、体外重组和遗传操作的应用，以鉴定和表征负责促毒细胞溶素生物合成的基因簇。这个家族中最著名的毒素是高度修饰的肽，链球菌溶血素S（SLS，由化脓性链球菌产生）。SLS的产生是感染过程所必需的，而不是生命过程所必需的。我们的工作已经发现，SLS样毒素至少由其他三种臭名昭著的人类病原体合成，包括金黄色葡萄球菌、单核细胞增生李斯特菌和肉毒梭菌。我们的目标是研究SLS样毒素在另一种生物体中的潜在作用，即导致莱姆病的伯氏疏螺旋体（Bb）。虽然广为人知，但Bb发病机制的分子机制是不充分的定义。如果在Bb感染期间确实使用了SLS样毒素，这将代表该生物家族中毒素利用的首次证明，并将促使疏螺旋体病的重大修订。 由于细菌通常采用不同的致病机制，保守的SLS样途径提供了一个难得的机会，以开发更广泛适用的，但有针对性的对策。从我们的角度来看，新的抗菌策略应该直接针对致病机制，而不是DNA复制，蛋白质合成或细胞壁。这种方法具有巨大的潜力，因为这些药物理论上可以抵抗耐药性。本项目将鉴定SLS毒素生物合成的抑制剂，用于开发新型抗菌药物的特定目的。此外，SLS是非免疫原性的，使其成为疫苗开发的不可行候选物。我们已经成功地产生了减毒变体，预期这些变体可用于提高毒素中和抗体。对细菌毒素免疫的概念代表了未来疫苗开发的潜在一般策略。 有了这个提议，我们的目标不仅是从根本上改变Bb发病机制的公认观点，而且挑战抗生素必须杀死细菌和非免疫原性毒素是棘手的疫苗候选人的范式。这些看似无关的目标实际上是相互交织的。我们的方法基于这样一种理念，即对毒素生物合成途径和化学结构的更完整理解可以合理地用于设计新的治疗方法。 公共卫生相关性：细菌病原体采用多种机制逃避人类免疫系统。我们已经发现了一种新的策略，导致莱姆病，谁的发病机制在很大程度上仍然是谜。更好地了解这些过程将为开发下一代抗菌药物奠定基础。

DESCRIPTION (Provided by the applicant) Abstract: The 20th century witnessed several major advances in medicine. Perhaps most important were the discovery of antibiotics for bacterial infections and effective vaccines for several major viruses. Unfortunately, the creation of effective vaccines for bacteria has lagged behind analogous anti-viral strategies. Compounded with the rise in antibiotic resistance and a lack of interest from the pharmaceutical industry in pursuing novel antibiotics, we risk losing the fight against bacterial pathogens. Described herein is an unconventional strategy to exploit bacterial toxins as both novel targets for antibacterial agents and antigens for vaccine development. To intelligently address the increasing threat posed by bacterial pathogens, more effort is needed to uncover the molecular underpinnings of virulence. Our group specializes in the use of bioinformatics, in vitro reconstitution, and genetic manipulation to identify and characterize gene clusters that are responsible for the biosynthesis of virulence- promoting cytolysins. The best-known toxin in this family is the highly modified peptide, streptolysin S (SLS, produced by Streptococcus pyogenes). SLS production is required for the infective process, but not essential life processes. Our work has uncovered SLS-like toxins are synthesized by at least three other notorious human pathogens, including Staphylococcus aureus, Listeria monocytogenes, and Clostridium botulinum. We aim to study the potential role of the SLS-like toxin in an additional organism, Borrelia burgdorferi (Bb), which causes Lyme disease. Although widely known, the Bb molecular mechanism of pathogenesis is inadequately defined. If the SLS-like toxin was indeed employed during Bb infections, this would represent the first demonstration of toxin utilization in this family of organisms and would prompt a major revision of borrelioses. Because bacteria typically employ disparate pathogenic mechanisms, the conserved, SLS-like pathway provides a rare opportunity to develop more broadly applicable, yet targeted countermeasures. From our perspective, new antimicrobial strategies should directly target the pathogenic mechanism, rather than DNA replication, protein synthesis, or the cell wall. This approach holds enormous potential, as these drugs will theoretically be resistant to resistance. This project will identify inhibitors of SLS toxin biosynthesis for the specific purpose of developing novel antibacterials. Moreover, SLS is non-immunogenic, rendering it an unfeasible candidate for vaccine development. We have succeeded in generating attenuated variants with the anticipation that these can be used for raising toxin-neutralizing antibodies. The notion of immunizing against a bacterial toxin represents a potentially general strategy for future vaccine development. With this proposal, we aim to not only fundamentally shift the accepted view of Bb pathogenesis, but also to challenge the paradigm that antibiotics must kill bacteria and non-immunogenic toxins are intractable vaccine candidates. These seemingly unrelated goals are actually quite intertwined. Our approach rests on the philosophy that a more complete understanding of toxin biosynthetic pathways and chemical structure can be rationally exploited to design novel therapeutics. Public Health Relevance: Bacterial pathogens employ numerous mechanisms to evade the human immune system. We have discovered a novel strategy within the organism that causes Lyme Disease, who's pathogenesis remains largely enigmatic. A greater understanding of these processes will lay the foundation for developing the next generation of antimicrobial drugs.