Development and Field Testing of a Novel Reservoir Targeted Antibiotic Against Borrelia burgdorferi

新型水库靶向伯氏疏螺旋体抗生素的开发和现场测试

• 批准号: 10397615
• 负责人: Linden T Hu
• 金额: $ 76.19万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397615
• 关键词: Anaplasma; Anaplasma phagocytophilum; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Area; Awareness; Bacteria; Biology; Borrelia burgdorferi; Clinical; Collaborations; Data; Deer; Development; Diagnosis; Disease; Disease Reservoirs; Dose; Doxycycline; Drug Kinetics; Eating; Environment; Evaluation; Excision; Exposure to; Financial cost; Food; Formulation; Genes; Geographic Distribution; Geography; Goals; Growth; Habitats; Health; Human; Incidence; Infection; Infection Control; Ingestion; Island; Ixodes; Laboratories; Lead; Life; Lyme Disease; Mammals; Manufacturer Name; Massachusetts; Measures; Modification; Mus; Oral; Oral Administration; Organism; OspA protein; Peptidyltransferase; Peromyscus; Pharmacodynamics; Politics; Population; Public Health; Recombinant Proteins; Recovery; Resistance; Resistance development; Resources; Ribosomes; Rocky Mountain Spotted Fever; Rodent; Safety; Salmonella; Soil; Source; Specificity; Streptomyces; Test Result; Testing; Ticks; Tilia; Toxic effect; United States; Vaccination; Vaccines; acaricide; base; design; dosage; drug development; experimental study; exposed human population; field study; genome sequencing; human disease; human pathogen; hygromycin A; infection rate; inhibitor; microorganism; mutant; novel; novel strategies; pathogen; simulation; stem; success; tool; uptake; vector; vector tick; weapons; whole genome

The incidence and geographic distribution of Lyme disease in the U.S. has increased steadily since its first description in 1977. Efforts to stem the spread of the disease through controlling the population of its tick vector and/or the mouse reservoirs of the disease have met with only limited success. The only approved human vaccine to protect against Lyme disease was removed from the market by its manufacturer further highlighting the need for new approaches to controlling the disease. In this project, we propose the development of a novel antibiotic targeted towards the mouse and tick reservoirs of the disease. This proposal combines the expertise in drug development of Dr. Kim Lewis’ laboratory, the expertise in Borrelia burgdorferi biology in Dr. Linden Hu’s laboratory and the field expertise of Dr. Sam Telford’s laboratory. Treatment of mice with an antibiotic, doxycycline, has been shown to be highly effective in eradicating Borrelia burgdorferi from its reservoir hosts. However, there is legitimate concern for development of resistance, both in B. burgdorferi and in other organisms that may be exposed to the antibiotic should it be widely distributed. Doxycyline is an important antibiotic in the treatment of multiple different human infections and in some cases such as Anaplasma or Rocky Mountain Spotted Fever, the only approved agent available. We have identified an antibiotic, hygromycin A (HygA), that is highly active against B. burgdorferi but has limited activity against other human pathogens. Its mechanism of action is different from other human antibiotics. In our preliminary data, we have shown that it is very effective in clearing B. burgdorferi from infected mice when given orally by gavage or in bait formulations. In this proposal, we will complete the steps in developing HygA as an environmental antibiotic and perform a limited field trial on an isolated island off the coast of MA to test its ability to control infection rates in ticks and mice. In Aim 1, we will establish the pharmacodynamics, stability and safety profile of HygA in Peromyscus mice. We will determine optimum concentrations for bait distribution and perform simulation studies of bait uptake and clearance in caged animals. In Aim 2, we will attempt to induce resistance to HygA in B. burgdorferi and in other organisms of human importance that are likely to encounter HygA in the environment. We will confirm that if HygA resistance develops, it does not cause concomitant resistance to other antibiotics with human applications. Finally, in Aim 3, we will perform a limited field trial on an isolated island that is endemic for B. burgdorferi in ticks and mice to establish the efficacy of a HygA based reservoir targeted antibiotic approach. This study has the potential to have a major impact on human Lyme disease by controlling the organism in its major reservoirs. By utilizing an antibiotic that has a narrow spectrum of activity and does not have human applications, we hope to replicate the success seen with doxycycline, which is arguably the most successful trial of any environmental approach to eradication to date, without the attendant concerns for resistance.

莱姆病在美国的发病率和地理分布自第一次发病以来一直稳步上升。 1977年的描述通过控制蜱虫数量来阻止疾病传播的努力 载体和/或疾病的小鼠储库仅取得有限的成功。唯一获批的 预防莱姆病的人类疫苗被其制造商从市场上撤下， 强调需要新的方法来控制这种疾病。 在这个项目中，我们提出了一种针对小鼠和蜱的新型抗生素的开发 疾病的储存库。该提案结合了金刘易斯博士在药物开发方面的专业知识， 林登胡博士实验室在伯氏疏螺旋体生物学方面的专业知识和 博士山姆·特尔福德的实验室用抗生素多西环素治疗小鼠，已被证明具有高度的 有效地将伯氏疏螺旋体从其宿主中根除。然而，人们有理由担心 在B中均出现耐药性。在可能暴露于抗生素的其它生物体中 如果它被广泛传播。强力霉素是一种重要的抗生素，在治疗多种不同的人类 感染和在某些情况下，如无形体或落基山斑点热，唯一批准的代理 available.我们已经鉴定了一种抗生素，潮霉素A（HygA），它对B具有高度活性。布格多费里湖 对其他人类病原体的活性有限。它的作用机制不同于其他人类 抗生素在我们的初步数据中，我们已经表明它在清除B方面非常有效。从Burgdorferi 感染的小鼠，通过灌胃或在诱饵制剂中口服给药。在本提案中，我们将完成以下步骤 在开发HygA作为环境抗生素，并进行了有限的现场试验，在一个孤立的岛屿关闭 在马萨诸塞州海岸测试其控制蜱和小鼠感染率的能力。 在目标1中，我们将在Peromyscus小鼠中建立HygA的药效学、稳定性和安全性特征。 我们将确定最佳浓度的诱饵分布和执行模拟研究的诱饵吸收 和清除率。在目标2中，我们将尝试在B中诱导对HygA的抗性。Burgdorferi和in 在环境中可能遇到HygA的其他对人类重要的生物。我们将确认 如果HygA耐药性发展，它不会引起人类对其他抗生素的伴随耐药性， 应用.最后，在目标3中，我们将在B流行的孤岛上进行有限的实地试验。 在蜱和小鼠中检测伯氏螺旋体以建立基于HygA的储库靶向抗生素方法的功效。 这项研究有可能对人类莱姆病产生重大影响， 主要水库。通过使用具有窄谱活性且不具有人源性的抗生素， 应用，我们希望复制与多西环素，这可以说是最成功的成功所看到的成功 迄今为止，对根除的任何环境方法进行了试验，而没有随之而来的耐药性问题。