High-throughput tandem-microwell assay for ammonia repositions FDA-Approved drugs to Helicobacter pylori infection

Abstract

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, i.e. 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 infecting 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.

Synthesis, characterization and urease inhibitory activities of Zn(II) complexes bearing C1-symmetric ligands derived from (R)-phenylethanamine

“…H. pylori releases high amount of its antigen, urease which cause an imbalance in overall ammonia level, thus causing severe infections, soil pH destabilization, ammonia volatilization and damaging of the plant roots [4]. Urease, a nickel containing metallo-enzyme, catalyzes the hydrolysis of urea into ammonia and carbamic acid which spontaneously decompose to yield a second molecule of ammonia and carbon dioxide thus resulting of elevation in pH and enabling H. pylori to survive in the extreme acidic conditions of stomach [5][6][7][8]. This bacterium is known to have caused infection in almost 50% of the population in developing countries [9][10][11].…”