NIH Director's Pioneer Award

尽管抗生素和疫苗取得了惊人的成功，但传染病仍然存在。 是世界范围内的主要死因之一多重耐药的出现 细菌已经造成了一种情况，其中很少或根本没有治疗某些 感染.现有疫苗的内在局限性（成本、安全性、保质期等）和 目前主要制药公司放弃抗生素和疫苗的趋势 发展计划造成了令人震惊的局面，潜在的灾难性公共 健康后果。 这一全球生物医学问题的根本解决方案和 拟议的研究是发展概念上的新方法，以防止和 治疗传染病。 一种通用策略是创造一种新型的全合成抗菌剂， 细菌很难产生耐药性。至少一 原型，一个基于5-氨基萘磺酰胺（ANSA）的化学平台， 在我们的实验室里被设计出来作为原理验证。与大多数抗生素不同， 针对单个大分子，ANSA化合物不可逆地损害各种 蛋白质，从而迅速杀死靶细胞。这个过程需要一氧化氮（NO）。 内源性NO足以使细菌对ANSA敏感，而外源性NO (e.g.来自巨噬细胞）进一步刺激杀菌作用。的组合 将选择最有效的ANSA和相关化合物，以确定 对不同病原菌种的特异性。 第二种一般方法涉及创建基于益生菌的疫苗。 益生菌是在宿主体内定殖或暂时存活的活细菌， 从而对其健康产生有益的影响。稳定和可控地分泌或 各种病原体的展示抗原可以有效地用作自我维持的疫苗。 作为原理验证，我们将设计益生菌菌株， 小鼠将诱导适当的免疫应答， 致命感染

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.