NIH Director's Pioneer Award

NIH 院长先锋奖

• 批准号: 7195522
• 负责人: EVGENY A NUDLER
• 金额: $ 84.5万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195522
• 关键词: NIH Roadmap Initiative tag; amino group; antiinfective agents; bioengineering /biomedical engineering; biotherapeutic agent; chemical synthesis; combinatorial chemistry; communicable diseases; disease /disorder prevention /control; multidrug resistance; naphthalenes; sulfonamides; technology /technique development; vaccine development

Despite the phenomenal success of antibiotics and vaccines, infectious diseases remain one of the leading cause of death worldwide. The emergence of multidrug-resistant bacteria has created a situation in which there are few or no options for treating certain infections. The intrinsic limitations of existing vaccines (cost, safety, shelf-life, etc.) and the current trend in major pharmaceutical companies to abandon antibiotic and vaccine development programs create an alarming situation with potentially catastrophic public health consequences. The radical solution for this global biomedical problem and the goal of the proposed research is the development of conceptually new approaches to prevent and treat infectious diseases. One general strategy is to create a new type of fully synthetic antimicrobials for which it would be intrinsically difficult for bacteria to develop resistance. At least one prototype, a chemical platform based on 5-aminonaphthalenesulfonamides (ANSA), has been designed in our laboratory as a proof-of-principle. Unlike the majority of antibiotics that target individual macromolecules, ANSA compounds irreversibly damage various proteins at once, thus rapidly killing a target cell. This process requires nitric oxide (NO). Endogenous NO is sufficient to render bacteria susceptible to ANSA, and exogenous NO (e.g. from macrophages) further stimulates the bactericidal effect. The combinatorial selection of the most potent ANSA and related compounds will be carried out to define the specificity for different pathogenic bacterial species. The second general approach involves creating probiotic-based vaccines. Probiotics are live bacteria that colonize or temporarily survive in the host, while conferring beneficial effect on its health. Probiotics that stably and controllably secrete or display antigens for various pathogens could effectively serve as self-sustaining vaccines. As a proof-of-principle we will engineer probiotic strains that upon oral administration to mice will induce a proper immune response rendering animals resistant to otherwise lethal infections.

尽管抗生素和疫苗取得了惊人的成功，但传染病仍然存在 全球死亡的主要原因之一。抗多药的出现 细菌创造了一种情况，在这种情况下，几乎没有或没有选择来治疗某些的情况 感染。现有疫苗的内在局限性（成本，安全，保质期等）和 主要制药公司放弃抗生素和疫苗的当前趋势 开发计划在潜在的灾难性公众中创造了令人震惊的情况 健康后果。 这个全球生物医学问题的激进解决方案和 拟议的研究是从概念上开发预防和 治疗传染病。 一种一般策略是为创建一种新型的完全合成抗菌剂 细菌在本质上很难发展抗性。至少一个 原型是一种基于5-氨基甲乙烯甲酰胺（ANSA）的化学平台，具有 在我们的实验室中设计为原则证明。与大多数抗生素不同 该靶向单个大分子，ANSA化合物不可逆转地损害了各种 蛋白质立即迅速杀死靶细胞。此过程需要一氧化氮（NO）。 内源性NO足以使细菌容易受到ANSA的影响，外源性NO （例如，巨噬细胞）进一步刺激杀菌作用。组合 选择最有效的ANSA和相关化合物以定义 不同致病细菌物种的特异性。 第二种一般方法涉及创建基于益生菌的疫苗。 益生菌是活在宿主中殖民或暂时生存的活细菌，而 赋予其健康有益影响。益生菌可稳定，可控性地分泌或 用于各种病原体的抗原可以有效用作自我维持的疫苗。 作为原理证明，我们将设计口服时的益生菌菌株 小鼠将诱导适当的免疫反应，使动物具有抵抗力 致命感染。