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)生物标记物的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病原体或宿主靶标的识别、表征和评估。细菌感染治疗中的一个主要挑战是出现抗生素耐药性。广泛分布的、保守的细菌毒力蛋白家族可能是新型抗菌剂的理想靶点。抑制毒力蛋白会导致细菌变弱，更容易被人类免疫系统清除。我们已经确定了一条细菌途径，这是毒力蛋白大家族发挥功能所必需的。这些自身转运蛋白广泛分布于革兰氏阴性细菌中。它们在细菌极分泌，这是它们正常分泌和发挥功能所必需的过程；因此，极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点。我们已经开发了一种报告试验，使我们能够确定模型自身转运体ICSA是否定位于细菌极点。我们在这一应用中的目标是使用这一测试来识别抑制这一毒力蛋白家族的分子，然后优化这些分子来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.鉴定抑制自身转运蛋白定位到细菌极点的小分子；以及目标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。由于自身转运蛋白对细菌的生存不是必不可少的，针对这一途径的抗生素可能会最低限度地选择用于微生物耐药性的发展。此外，由于真核生物中没有自体转运蛋白，因此至少一些被发现具有抗自体转运蛋白活性的化合物可能不会对哺乳动物细胞产生不良影响。最后，如果它们不能发展成抗生素，这项提议中确定和表征的小分子将构成有价值的药理学工具，用于研究自体转运蛋白，也许还有其他极性蛋白，定位到细菌极点的基本机制。 与公共卫生相关：治疗细菌感染的一个主要挑战是出现抗生素耐药性；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。我们已经确定了一条细菌途径，这是毒力蛋白大家族发挥功能所必需的。我们在这一应用中的目标是识别抑制这一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.