Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, Sheng Yushou Center of Cell Biology and Immunology, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
FASEB J. 2021 Nov;35(11):e21967. doi: 10.1096/fj.202100465RR.
To date, little attempt has been made to develop new treatments for Helicobacter pylori (H. pylori), although the community is aware of the shortage of treatments for H. pylori. In this study, we developed a 192-tandem-microwell-based high-throughput assay for ammonia that is a known virulence factor of H. pylori and a product of urease. We could identify few drugs, that is, panobinostat, dacinostat, ebselen, captan, and disulfiram, to potently inhibit the activity of ureases from bacterial or plant species. These inhibitors suppress the activity of urease via substrate-competitive or covalent-allosteric mechanism, but all except captan prevent the antibiotic-resistant H. pylori strain from killing human gastric cells, with a more pronounced effect than acetohydroxamic acid, a well-known urease inhibitor and clinically used drug for the treatment of bacterial infection. This study offers several bases for the development of new treatments for urease-containing pathogens and to study the mechanism responsible for the regulation of urease activity.
迄今为止，尽管人们已经意识到治疗幽门螺杆菌（H. pylori）的方法有限，但针对该细菌的新疗法的研究仍然寥寥无几。在本研究中，我们开发了一种基于 192 孔微阵列的高通量氨检测法，该方法检测的氨是 H. pylori 的一种已知毒力因子，也是脲酶的产物。我们发现了一些能够有效抑制细菌或植物来源的脲酶活性的药物，包括帕比司他、西达司他、依布硒啉、克菌丹和双硫仑。这些抑制剂通过底物竞争或共价变构机制抑制脲酶的活性，但除了克菌丹之外，其他抑制剂都不能阻止抗生素耐药的 H. pylori 菌株杀死人类胃细胞，其效果比乙酰氧肟酸更为显著，后者是一种已知的脲酶抑制剂，也是临床上用于治疗细菌感染的药物。本研究为开发含有脲酶的病原体的新疗法以及研究脲酶活性调节机制提供了多个依据。
