Discovery of three types of new drug leads against infection of drug-resistant Helicobacter Pylori strains
Background: Helicobacter pylori is a pathogenic bacterium that can cause gastric cancer. More than 50% of the world's population has been infected by Helicobacter pylori. At present, clinical first-line drugs mainly use amoxicillin, metronidazole, clarithromycin antibiotics, proton pump inhibitors, and bismuth agents in combination to inhibit the growth and infection of the bacteria (commonly known as triple method or quadruple method). In recent years, Helicobacter pylori has strong resistance to these known antibiotics, making the eradication of Helicobacter pylori a thorny issue in clinical practice.
The Wu Fang research group of the Shanghai Jiaotong University System Biomedical Research Institute aimed at the drug target urease of Helicobacter pylori, based on the high-throughput H2S gas detection technology independently designed and developed by the research group before that is the 192 tandem two-well plate (Chem. Comm. 2013; Has Authorized 2018 Chinese invention patent CN201310467388.1), developed a new high-throughput parallel method for the detection of urease NH3 gas products. Using this method, the first high-throughput screening of urease inhibitors was carried out. Through the screening of about 4,000 FDA-approved or clinically researched small molecule drugs, three types of old drugs (Panobinostat, Ebselen and Disulfiram) were found to inhibit the pylorus. Helicobacter urease activity, the growth of the bacteria and its infection of the epithelial cells of the gastrointestinal tract. By cooperating with Yu Jing's group from the School of Life Science and Technology, Shanghai Jiaotong University, Wu Xinyan's group from the School of Chemistry and Molecular Engineering, East China University of Science and Technology, Xu Jinyi's group from the Department of Pharmacy, China Pharmaceutical University, and the analysis and creation of the Hunan Engineering Laboratory of National Medicine in Wulingshan Region of Jishou University The multidisciplinary cooperation between Xiao Zhuping's group and Liao Lujian's group from the School of Life Sciences, East China Normal University confirmed the molecular mechanism, site of action, and structure-activity relationship of these three types of old drugs to inhibit urease.
The study found that the old HDAC inhibitor Panobinostat is a substrate competitive inhibitor of urease; the old drug Ebselen containing selenium atoms can allosterically covalently modify the Cys313 residue of the enzyme to non-competitively inhibit the enzyme activity; Disulfiram, an old drug for abstinence from alcohol, inhibits the enzyme by forming a complex with the metal prosthetic group Ni2+ of the enzyme. The IC50 values of these compounds (respectively: 100 nM; 2.8 microM; 8.9 microM) are nearly 259, 10, and 8 times higher than the FDA-approved known inhibitor of urease, acetohydroxamic acid (IC50 of 25.9 microM). At the same time, these drug leaders are more effective than acetohydroxamic acid in inhibiting the infection of gastrointestinal epithelial cells by resistant Helicobacter pylori bacteria. Because the old drugs Ebselen, Disulfiram and their new derivatives inhibit the drug-resistant bacteria, the minimum inhibitory constant is 2-4 microgram/ml, which is equivalent to the effectiveness of the known antibiotic clarithromycin, indicating that these old drugs can As a drug candidate for the treatment of drug-resistant Helicobacter pylori infection.
Legend：The first drug screening campaign to identify new inhibitors of ureases.
The article entitled "High- throughput tandem- microwell assay for ammonia repositions FDA- Approved drugs to inhibit Helicobacter pylori urease. https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202100465RR)" will be published in 2021 It was formally published online on October 6, 2015. Master students Liu Fan and Associate Researcher Yu Jing are the first authors. This work was funded by the National Natural Science Foundation of China and the Shanghai Natural Science Foundation of China.