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

项目摘要 巴贝斯虫病是美国一种新出现的人畜共患病，当患者感染 巴贝虫通过蜱传播，是莱姆病的常见合并感染。这种疾病可以 由各种巴氏杆菌属的感染引起，导致从无症状感染到 严重和危及生命的疾病。目前巴贝斯虫病的治疗选择要么有严重的副作用， 由于寄生虫产生抗药性，治疗失败的风险很高。巴氏疟原虫的生物学 目前对这一问题的研究仍然很少，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的方法，以快速，有效地确定小的基本目标， 分子抑制剂在多种巴贝虫属中的应用我们将审问两个巴氏杆菌属。可以在体外培养。 我们将选择对高优先级小 分子抑制剂，使用化学诱变来加速这一过程， 产生抵抗力。为了验证和研究这些抑制剂的分子靶点，我们将产生 研究B中必需蛋白质所需的遗传和生物学工具。分歧，并展示他们的 通过PhoDapi的遗传验证有效性，PhoDapi是我们实验室使用 对MMV019266的耐药性演变。

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.