A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection.
复制标题
小分子筛选鉴定出抗精神病药物匹莫齐特是单核细胞增生李斯特菌感染的抑制剂。
DOI：
10.1128/aac.00607-08
复制
发表时间：
2009
影响因子：
4.9
通讯作者：
Higgins,DarrenE
中科院分区：
文献类型：
--
作者：
Lieberman,LindaA;Higgins,DarrenE
We developed a screening procedure to identify small-molecule compounds that altered infection byListeria monocytogenesto gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered theL. monocytogenesinfection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape ofL. monocytogenesin BMM. The inhibitory effect of pimozide on internalization was not specific forL. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis,Salmonella entericaserovar Typhimurium, andEscherichia coliK12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread ofL. monocytogenesduring the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide onL. monocytogenesinfection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
