Novel Therapy for Staphylococcal Infection

耐药金黄色葡萄球菌的出现 迫切需要新的治疗方法来治疗 由这种常见病原体引起的各种疾病。S.金黄色葡萄球菌损害 宿主组织通过分泌多种已知的有毒外泌分子 毒力因子。这些因素的表达是由一个 自分泌调节系统，借此细菌分泌自诱导 信息素肽作用于细胞以上调 一组编码毒力因子的基因。这项建议是根据 偶然发现一种修饰的肽污染了一批 合成信息素肽的基础上的非- 葡萄球菌的致病菌株。这种肽，叫做毒力 抑制因子（VIF），抑制α毒素的合成和毒性 休克综合征毒素在所有测试的葡萄球菌菌株。进一步 研究表明，VIF的小分子类似物抑制了毒力， 因子的体外生产，并保护小鼠免受致命的系统性S。 金黄色葡萄球菌感染。本提案的目标是评估一个大型小组 小VIF类似物在体外，并选择最佳的候选药物， 进一步的研究在体内。拟议的研究包括药理学， 毒理学和各种S.金黄色葡萄球菌感染 这种新的治疗方法有希望在 耐药葡萄球菌的治疗 拟议的商业应用： 由于耐药葡萄球菌菌株的出现，许多 感染不能用常规抗生素治疗。的 葡萄球菌的致病机理感染取决于毒力的产生 促进细菌定植并对宿主有毒的因素 组织中本申请提出开发一种新的药物， 抑制毒力因子的产生，并且应该对 耐抗生素葡萄球菌

The emergence of antibiotic-resistant Staphylococcus aureus has created an urgent need for new therapeutic approaches to treat the variety of diseases caused by this common pathogen. S. aureus damages host tissues by the secretion of a variety of toxic exomolecules known as virulence factors. The expression of these factors is controlled by an autocrine regulatory system whereby bacteria secrete autoinducing pheromone peptides that act on the cell to upregulate expression of the set of genes encoding virulence factors. This proposal is based on the serendipitous discovery of a modified peptide contaminating a batch of synthetic pheromone peptide based on the sequence of a non- pathogenic strain of Staphylococcus. This peptide, called virulence inhibitory factor (VIF), inhibited synthesis of alpha toxin and toxic shock syndrome toxin in all Staphylococcal strains tested. Further studies revealed that small molecule analogs of VIF inhibited virulence factor production in vitro and protected mice from a lethal systemic S. aureus infection. The goal of this proposal is to evaluate a large panel of small VIF analogs in vitro and select the best drug candidate for further studies in vivo. Proposed studies include pharmacology, toxicology, and various animal models of S. aureus infection in preparation of an IND. This novel therapeutic approach has promise in the treatment of antibiotic-resistant Staphylococci. PROPOSED COMMERCIAL APPLICATIONS: Due to the emergence of drug-resistant strains of Staphylococci, many infections are not treatable with conventional antibiotics. The pathogenesis of Staph. infections depend on the production of virulence factors that promote bacterial colonization and are toxic to the host tissues. The present application proposes to develop a novel drug that inhibits production of virulence factors and should be therapeutic to antibiotic resistant Staph.