Developing comparative chemical genomics and genetic validation tools for Babesia spp.

项目概要 巴贝虫病是美国一种新出现的人畜共患疾病，当患者感染巴贝虫病时就会发生这种疾病。 巴贝虫寄生虫通过蜱传播，是莱姆病的常见合并感染。该病可 由各种巴贝虫属感染引起，导致从无症状感染到各种症状 严重且危及生命的疾病。目前巴贝斯虫病的治疗方案要么具有严重的副作用，要么 由于寄生虫产生耐药性，治疗失败的风险很高。巴贝虫寄生虫的生物学 仍然缺乏研究，部分原因是缺乏可用的遗传和生物工具。 在这里，我们建议建立一种新方法来快速有效地识别小规模的基本目标 多种巴贝虫属的分子抑制剂。我们将询问两种巴贝虫属。可以在体外培养。 我们将选择对高优先级小分子具有抗性的分歧巴贝斯虫和牛巴贝斯虫寄生虫品系。 分子抑制剂，使用化学诱变来加速这一过程并增加可能性 产生抵抗力。为了验证和研究这些抑制剂的分子靶点，我们将生成 研究分歧芽孢杆菌必需蛋白质所需的遗传和生物学工具，并证明它们的作用 通过 PhoDapi 的基因验证功效，PhoDapi 是我们实验室使用的方法确定的假定目标 针对 MMV019266 的耐药性进化。

Project Summary Babesiosis is an emerging zoonotic disease in the United States, that occurs when a patient is infected with a Babesia parasite by transmission from ticks, and is a common co-infection of Lyme disease. The disease can result from infection with various Babesia spp., resulting in everything from an asymptomatic infection to severe and life-threatening disease. Current treatment options for babesiosis either have severe side effects or a high risk of treatment failure due to the parasite developing drug resistance. The biology of Babesia parasites remains poorly studied, in part due to a lack of genetic and biological tools available. Here, we propose to establish a new approach to rapidly and efficiently identify essential targets of small molecule inhibitors in multiple Babesia spp. We will interrogate two Babesia spp. that can be cultured in vitro. We will select for Babesia divergens and Babesia bovis parasite lines that are resistant to high priority small molecule inhibitors, using chemical mutagenesis to accelerate the process and increase the likelihood of developing resistance. In order to validate and study the molecular targets of these inhibitors, we will generate the required genetic and biological tools to study essential proteins in B. divergens, and demonstrate their efficacy through the genetic validation of PhoDapi, the putative target identified by our laboratory using resistance evolution against MMV019266.