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 世界范围内的主要死因之一。多药耐药的出现 细菌造成了一种情况，在这种情况下，治疗某些特定疾病的选择很少，甚至没有选择 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 发展项目造成了一种令人震惊的局面，可能会对公众造成灾难性影响 对健康的影响。 这一全球性生物医学问题的根本解决方案和 拟议的研究是开发概念上的新方法来预防和 治疗传染病。 一种普遍的策略是创造一种新型的全合成抗菌剂 这对细菌来说是很难产生抗药性的。至少一个 Prototype是一种基于5-氨基萘磺酰胺(ANSA)的化学平台，它具有 在我们的实验室里被设计成一个原则证明。与大多数抗生素不同 以单个大分子为目标，ANSA化合物不可逆转地损害各种 蛋白质，从而迅速杀死目标细胞。这一过程需要一氧化氮(NO)。 内源性NO足以使细菌对ANSA敏感，而外源性NO足以使细菌对ANSA敏感 (例如来自巨噬细胞)进一步刺激杀菌效果。组合式 将进行最有效的ANSA和相关化合物的选择，以确定 对不同病原菌种类的特异性。 第二种一般方法涉及创造以益生菌为基础的疫苗。 益生菌是在宿主体内定居或暂时存活的活细菌，而 对它的健康产生有益的影响。稳定且可控制地分泌或 各种病原体的展示抗原可以有效地作为自给自足的疫苗。 作为一项原则证明，我们将改造益生菌菌株，使其在口服后 小鼠会诱导适当的免疫反应，使动物对其他免疫反应产生抵抗力 致命的感染。

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.