Uddin Taher, Xia Jing, Fu Yong, McNamara Case W, Chatterjee Arnab K, Sibley L David
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
Calibr at Scripps Research, La Jolla, California, USA.
bioRxiv. 2024 Aug 22:2024.07.01.601569. doi: 10.1101/2024.07.01.601569.
causes widespread chronic infections that are not cured by current treatments due to inability to affect semi-dormant bradyzoite stages within tissue cysts. To identify compounds to eliminate chronic infection, we developed a HTS using a recently characterized strain of that undergoes efficient conversion to bradyzoites in intro. Stage-specific expression of luciferase was used to selectively monitor growth inhibition of bradyzoites by the Library of Pharmacological Active Compounds, consisting of 1,280 drug-like compounds. We identified 44 compounds with >50% inhibitory effects against bradyzoites, including new highly potent compounds, several of which have precedent for antimicrobial activity. Subsequent characterization of the compound Sanguinarine sulfate revealed potent and rapid killing against in vitro produced bradyzoites and bradyzoites harvested from chronically infected mice. These findings provide a platform for expanded screening and identify promising compounds for further preclinical development against bradyzoites responsible for chronic infection.
由于无法影响组织囊肿内处于半休眠状态的缓殖子阶段，导致广泛的慢性感染无法通过当前治疗治愈。为了鉴定能够消除慢性感染的化合物，我们利用最近鉴定的一种菌株开发了一种高通量筛选方法，该菌株在体外能高效转化为缓殖子。利用荧光素酶的阶段特异性表达来选择性监测由1280种类药物化合物组成的药理活性化合物库对缓殖子生长的抑制作用。我们鉴定出44种对缓殖子具有>50%抑制作用的化合物，包括新的高效化合物，其中几种具有抗菌活性的先例。随后对化合物硫酸血根碱的表征显示，它对体外产生的缓殖子和从慢性感染小鼠体内收获的缓殖子具有强大而快速的杀伤作用。这些发现为扩大筛选提供了一个平台，并确定了有前景的化合物，用于针对导致慢性感染的缓殖子进行进一步的临床前开发。
