Develop antibiotics that inhibit bacterial virulence proteins

描述（由申请人提供）：本申请涉及广泛的挑战领域（03）生物标志物发现和验证以及特定的挑战主题，03-AI-101：可能导致开发具有广谱活性的抗菌剂的新型病原体或宿主靶标的鉴定、表征和评价。治疗细菌感染的一个主要挑战是抗生素耐药性的出现。广泛分布的、保守的细菌毒力蛋白家族是新型抗菌剂的潜在理想靶点。毒力蛋白的抑制导致细菌减毒并且更容易被人类免疫系统清除。我们已经表征了一个大家族的毒力蛋白的功能所需的细菌途径。这些蛋白质，即自身转运蛋白，广泛分布于革兰氏阴性细菌病原体中。它们在细菌极点分泌，这是其正常分泌和功能所需的过程;因此，极性靶向途径为开发利用独特作用机制的新型抗生素提供了理想的靶标。我们已经开发了一种报告分析，使我们能够确定模型的自转运蛋白IcsA是否本地化或不细菌极。我们在本申请中的目标是使用该测定来鉴定抑制该毒力蛋白家族的分子，然后优化这些分子以抑制由这些细菌病原体引起的疾病。我们的具体目标如下：目标1。鉴定抑制自转运蛋白定位到细菌极的小分子;和目标2.优化化合物并研究其活性机制。我们的长期目标是开发一种利用独特作用机制的新型抗生素。由于自转运蛋白对细菌存活不是必需的，因此靶向该途径的抗生素可能最小限度地选择微生物耐药性的发展。此外，由于自体转运蛋白在真核生物中不存在，因此发现对自体转运蛋白有活性的至少一些化合物将可能对哺乳动物细胞没有不利影响。最后，短的抗生素的发展，小分子的鉴定和特点，在这个建议将构成有价值的药理学工具，调查本地化的基本机制的自转运蛋白，也许其他极性蛋白质，细菌极。 公共卫生相关性：治疗细菌感染的一个主要挑战是抗生素耐药性的出现;我们的长期目标是开发一种利用独特作用机制的新型抗生素。我们已经表征了一个大家族的毒力蛋白的功能所需的细菌途径。我们在本申请中的目标是鉴定抑制该毒力蛋白家族的分子，并优化这些分子以抑制由这些细菌病原体引起的疾病。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-AI-101: Identification, characterization and evaluation of novel pathogen or host targets that may lead to the development of antimicrobials with broad spectrum activity. A major challenge in the treatment of bacterial infections is the emergence of antibiotic resistance. Widely distributed, conserved families of bacterial virulence proteins are potentially ideal targets for novel antimicrobial agents. Inhibition of virulence proteins results in bacteria that are attenuated and more easily cleared by the human immune system. We have characterized a bacterial pathway that is required for function of a large family of virulence proteins. These proteins, the autotransporters, are widely distributed among gram-negative bacterial pathogens. They are secreted at the bacterial pole, a process that is required for their proper secretion and function; consequently, the polar targeting pathway presents an ideal target for the development of a novel category of antibiotics that utilize a unique mechanism of action. We have developed a reporter assay that enables us to determine whether the model autotransporter IcsA is localized or not to the bacterial pole. Our goal in this application is to use this assay to identify molecules that inhibit this family of virulence proteins and to then optimize these molecules for the inhibition of diseases caused by these bacterial pathogens. Our specific aims are as follows: Aim 1. Identify small molecules that inhibit autotransporter localization to the bacterial pole; and Aim 2. Optimize compounds and investigate their mechanisms of activity. Our long-term goal is to develop a novel category of antibiotics that utilize a unique mechanism of action. Since autotransporter proteins are not essential to bacterial survival, antibiotics that target this pathway are likely to minimally select for the development of microbial resistance. Moreover, since autotransporters are absent in eukaryotes, at least some of the compounds that are found to be active against autotransporters will likely have no adverse effects on mammalian cells. Finally, short of their development into antibiotics, the small molecules identified and characterized in this proposal would constitute valuable pharmacological tools for investigations into the fundamental mechanism of localization of autotransporters, and perhaps other polar proteins, to the bacterial pole. PUBLIC HEALTH RELEVANCE: A major challenge in the treatment of bacterial infections is the emergence of antibiotic resistance; our long-term goal is to develop a novel category of antibiotics that utilize a unique mechanism of action. We have characterized a bacterial pathway that is required for the function of a large family of virulence proteins. Our goal in this application is to identify molecules that inhibit this family of virulence proteins and to optimize these molecules for the inhibition of diseases caused by these bacterial pathogens.