Targeting Cyclic Dinucleotide Signaling Pathways to Interrupt the Nature Cycle of Borrelia burgdorferi

靶向环状二核苷酸信号通路来中断伯氏疏螺旋体的自然循环

• 批准号: 10405644
• 负责人: Herman O Sintim
• 金额: $ 59.12万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-09 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405644
• 关键词: Address; Animals; Antibiotics; Area; Bacteria; Bacterial Physiology; Black-legged Tick; Borrelia burgdorferi; Chemicals; Chemistry; Data; Dinucleoside Phosphates; Disease Reservoirs; Doxycycline; Drug Targeting; Foundations; Health; Human; Incidence; Infection; Interruption; Lyme Disease; Mammals; Mus; Natural History; Nature; Order Spirochaetales; Outcome; Outcome Study; Pathway interactions; Patients; Periodicity; Prevention; Public Health; Radioactivity; Reactive Oxygen Species; Reporting; Research; Rodent; Second Messenger Systems; Signal Pathway; Signal Transduction; System; Testing; Tick-Borne Diseases; Ticks; Vaccines; Work; Yang; acaricide; diguanylate cyclase; drug discovery; enzootic; experimental study; infection rate; infection risk; inhibitor; pathogen; professor; screening; small molecule inhibitor; tick population; vector tick

Lyme disease has emerged as a major public health threat in the US. Currently, no human vaccine is available. Although targeting tick populations with chemical acaricides is an effective way of reducing the risk of infection, the use of acaricides has adverse health effects and raises environmental concerns. A host-targeted approach by deploying doxycycline hyclate-laden baits to the field showed dramatic reduction of infection rates in both rodent reservoirs and Ixodes scapularis ticks by Borrelia burgdorferi, the agent of Lyme disease. However, antibiotics such as doxycycline are not suitable for such purpose as they are used for treating patients. Nevertheless, such proof of concept study demonstrates that a host-targeted approach using alternative compounds is a promising approach to eliminate spirochetes in rodent reservoir hosts and tick vectors. The bacterial second messengers, c-di-GMP and c-di-AMP, have emerged as central regulators for bacterial physiology and are potential drug targets. Many bacteria encode multiple copies of cyclases for the synthesis of c-di-GMP and c-di-AMP, which make it difficult to target the pathways. Borrelia burgdorferi only has a single diguanylate cyclase Rrp1 and a single diadenylate cyclase CdaA for c-di-AMP synthesis, which makes them attractive drug targets. As shown in the preliminary data, we found that these two cyclic dinucleotide, one controls spirochetes’ survival in each of the two hosts in B. burgdorferi enzootic cycle, ticks and mammals: while c-di-GMP is essential for tick colonization, c-di-AMP is indispensable for mammalian infection. The hypothesis of this proposal is that small molecule inhibitors targeting c-di-GMP and c-di- AMP cyclases, Rrp1 and CdaA, would eliminate B. burgdorferi in ticks and mammalian reservoirs, which can be exploited to reduce Lyme disease incidence. The co-PI of this proposal, Dr. Herman Sintim, a Drug Discovery Professor of Chemistry, pioneered developing inhibitors for bacterial diguanylate cyclase and diadenylate cyclase, and his group has already reported several potent inhibitors against these cyclases of other bacteria. Accordingly, we propose to develop a strategy to target CdaA of B. burgdorferi to eliminate in spirochetes rodent reservoirs (Aim 1), and a strategy to target Rrp1 of B. burgdorferi to eliminate spirochetes in ticks (Aim 2). We will also test a combination of inhibitors targeting both pathways to eliminate B. burgdorferi in its enzootic cycle. The underlying mechanisms of how c-di-AMP and c-di-GMP are employed by B. burgdorferi to survive in mammals and ticks will also be investigate. This proposal address one of the specific Focus Areas listed in this RFA: reservoir-targeted approaches to interrupt the natural history of infection. Upon accomplishing the proposed work, further field experiments will be conducted using animal baits containing a combination of both inhibitors to evaluate their effects on reducing spirochete burden in ticks and animals in nature. Such host-targeted strategy will have significant impact on combating Lyme disease.

在美国，莱姆病已成为主要的公共卫生威胁。目前，没有人类疫苗可用。 尽管用化学急经剂靶向壁虱种群是降低感染风险的有效方法 使用急经剂具有不良的健康影响，并引起了环境问题。通过 将多西环素诱饵部署到田野上，显示出两种啮齿动物的感染率显着降低 莱姆病代理人Borrelia Burgdorferi的水库和ixodes肩cap虫。但是，抗生素也是如此 由于强力霉素不适合用于治疗患者的目的。然而，这样的证明 概念研究表明，使用替代化合物的宿主目标方法是一种有前途的方法 消除啮齿动物储层宿主和tick矢量中的螺旋体。细菌第二使者，C-DI-GMP和 C-DI-AMP已成为细菌生理学的中央调节剂，并且是潜在的药物靶标。许多细菌 编码多个循环的副本，以合成C-DI-GMP和C-DI-AMP，这使得很难靶向 路径。 Borrelia burgdorferi只有一个二烷基酸环化酶RRP1和一个单二丝淀粉环化酶 CDAA用于C-DI-AMP合成，这使它们成为有吸引力的药物靶标。如初步数据所示，我们发现 这是两个环状二核苷酸，一个人控制螺旋体在B. B. B. B. B. B.b。B. enzootic循环，tick和哺乳动物：虽然C-DI-GMP对于tick殖必不可少，但C-Di-Amp是必不可少的 哺乳动物感染。该提议的假设是针对C-DI-GMP和C-DI-a的小分子抑制剂 AMP周期，RRP1和CDAA将消除tick虫和哺乳动物的水库中的B. burgdorferi，这可以是 利用以减少莱姆病的事件。该提案的共同点，毒品发现赫尔曼·辛蒂姆（Herman Sintim）博士 化学教授，开创性开发的二甘氨酸二甘氨酸酸环化酶和二氨基甲基酸环化酶的抑制剂， 他的小组已经报告了几种对其他细菌周期的潜在抑制剂。根据 我们建议制定一种以B. burgdorferi的CDAA为目标的策略，以消除螺旋体啮齿动物储层（AIM 1），以及针对B. burgdorferi的RRP1的策略，以消除tick中的螺旋体（AIM 2）。我们还将测试 靶向两种途径以消除B.b。b.b. b. thecootic循环的抑制剂的组合。基础 B. burgdorferi如何利用C-DI-AMP和C-DI-GMP的机制，以在哺乳动物和壁虱中生存 也要调查。该提案介绍了此RFA中列出的特定焦点领域之一：以储层为目标 打断感染自然史的方法。完成拟议的工作后，进一步领域 实验将使用包含两种抑制剂组合的动物诱饵来评估其效果 关于减少自然界中tick虫和动物中的螺旋体伯恩。这种以主机为目标的策略将产生重大影响 在战斗莱姆病。