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: 10606624
• 负责人: Linden T Hu
• 金额: $ 75.41万
• 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/10606624
• 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; Experimental Designs; Exposure to; Financial cost; Food; Formulation; Genes; Geographic Distribution; Geography; Goals; Growth; Habitats; Health; Human; Incidence; Infection; Infection Control; Ingestion; Island; Ixodes; Laboratories; Lead; Lyme Disease; Mammals; Manufacturer; Marketing; Massachusetts; Measures; Modification; Mus; Oral; Oral Administration; Organism; OspA protein; Peptidyltransferase; Peromyscus; Pharmacodynamics; Politics; Population; Population Control; Public Health; Recombinant Proteins; Recovery; Resistance; Resistance development; Resources; Ribosomes; Rocky Mountain Spotted Fever; Rodent; Safety; Salmonella; Soil; Source; Specificity; Streptomyces; Test Result; Testing; Therapeutic; Ticks; Tilia; Toxic effect; United States; Vaccination; Vaccines; acaricide; disorder control; dosage; drug development; efficacy evaluation; 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; transmission process; 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.

自莱姆病首次出现以来，美国莱姆病的发病率和地理分布一直在稳步增加 1977 年的描述。通过控制蜱虫数量来阻止疾病传播 该疾病的媒介和/或小鼠宿主只取得了有限的成功。唯一获批的 用于预防莱姆病的人类疫苗进一步被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，我们建议开发一种针对小鼠和蜱的新型抗生素 疾病的储存库。该提案结合了 Kim Lewis 博士在药物开发方面的专业知识 实验室、Linden Hu 博士实验室的伯氏疏螺旋体生物学专业知识以及 萨姆·特尔福德博士的实验室。用抗生素强力霉素治疗小鼠已被证明具有很高的效果 能有效根除其储存宿主中的伯氏疏螺旋体。然而，有合理的担忧 伯氏疏螺旋体和其他可能接触抗生素的生物体中出现耐药性 是否应该广泛分发。多西环素是治疗多种不同人类疾病的重要抗生素 感染，以及在某些情况下，例如无形体或落基山斑疹热，这是唯一批准的药物 可用的。我们已经鉴定出一种抗生素潮霉素 A (HygA)，它对伯氏疏螺旋体具有高度活性，但 对其他人类病原体的活性有限。其作用机制与其他人类不同 抗生素。在我们的初步数据中，我们已经表明它对于清除伯氏疏螺旋体非常有效 当通过灌胃或诱饵制剂口服给药时，受感染的小鼠。在这个提案中，我们将完成以下步骤 开发 HygA 作为一种环境抗生素，并在离岛不远的一座孤岛上进行了有限的现场试验 马萨诸塞州海岸，测试其控制蜱虫和小鼠感染率的能力。 在目标 1 中，我们将建立 HygA 在 Peromyscus 小鼠中的药效学、稳定性和安全性特征。 我们将确定诱饵分布的最佳浓度并进行诱饵吸收的模拟研究 和笼养动物的清除。在目标 2 中，我们将尝试在伯氏疏螺旋体和 可能在环境中遇到 HygA 的其他对人类重要的生物体。我们将确认 如果 HygA 产生耐药性，不会导致人类对其他抗生素同时产生耐药性 应用程序。最后，在目标 3 中，我们将在 B.B. 流行的孤岛上进行有限的现场试验。 伯氏杆菌在蜱和小鼠中建立基于 HygA 的储库靶向抗生素方法的功效。 这项研究有可能通过控制体内的生物体对人类莱姆病产生重大影响 其主要水库。通过使用活性谱窄且对人类无害的抗生素 应用，我们希望复制多西环素的成功，这可以说是最成功的 迄今为止，对任何环境根除方法进行了尝试，没有随之而来的耐药性问题。

项目成果

Development of a capture sequencing assay for enhanced detection and genotyping of tick-borne pathogens.

开发捕获测序测定法，加强蜱媒病原体的检测和基因分型。

• DOI: 10.1038/s41598-021-91956-z
• 发表时间: 2021-06-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Jain K;Tagliafierro T;Marques A;Sanchez-Vicente S;Gokden A;Fallon B;Mishra N;Briese T;Kapoor V;Sameroff S;Guo C;Marcos LA;Hu L;Lipkin WI;Tokarz R
• 通讯作者: Tokarz R