Coptisine-induced inhibition ofHelicobacter pylori: elucidation of specific mechanisms by probing urease active site and its maturation process

Abstract

In this study, we examined the anti-Helicobactor pylori effects of the main protoberberine-type alkaloids in Rhizoma Coptidis. Coptisine exerted varying antibacterial and bactericidal effects against three standard H. pylori strains and eleven clinical isolates, including four drug-resistant strains, with minimum inhibitory concentrations ranging from 25 to 50 μg/mL and minimal bactericidal concentrations ranging from 37.5 to 125 μg/mL. Coptisine’s anti-H. pylori effects derived from specific inhibition of urease in vivo. In vitro, coptisine inactivated urease in a concentration-dependent manner through slow-binding inhibition and involved binding to the urease active site sulfhydryl group. Coptisine inhibition of H. pylori urease (HPU) was mixed type, while inhibition of jack bean urease was non-competitive. Importantly, coptisine also inhibited HPU by binding to its nickel metallocentre. Besides, coptisine interfered with urease maturation by inhibiting activity of prototypical urease accessory protein UreG and formation of UreG dimers and by promoting dissociation of nickel from UreG dimers. These findings demonstrate that coptisine inhibits urease activity by targeting its active site and inhibiting its maturation, thereby effectively inhibiting H. pylori. Coptisine may thus be an effective anti-H. pylori agent.

Chelerythrine Chloride: A Potential Rumen Microbial Urease Inhibitor Screened by Targeting UreG

“…Chelerythrine chloride is considered to be the most potential inhibitor of urease, with the lowest IC 50 and K i values and the highest binding energy. Li et al [ 34 ] demonstrated that when the final concentration of H. pylori UreG was 5 μM, the IC 50 value of coptisine was 89.86 μM. In this study, the IC 50 value of coptisine chloride was 86.62 μM, with a final concentration of 3 μM UreG, and the IC 50 value of 18.13 μM for chelerythrine chloride was significantly lower than that of coptisine chloride.…”

“…Yang et al [ 45 ] first proposed and confirmed that targeting the metallochaperone UreG to design urease inhibitors could disrupt the urease maturation process, and provided two effective urease inhibitors of colloidal bismuth against H. pylori activity only through UreG, not apo-urease. Li et al [ 34 ] demonstrated that coptisine inactivation of H. pylori urease involved binding to the urease active site sulfhydryl group and accessory protein UreG. These results show the potential of UreG serving as a target for developing urease inhibitors.…”

“…Considering the cost performance, application prospects, sources and categories of the compounds, isochlorogenic acid C and chelerythrine chloride were selected for further analysis. A previous experiment [34] demonstrated that coptisine could inhibit the function of UreG during urease maturation; thus, GTPase activity of UreG with coptisine chloride was used as a positive control during the measurement of IC 50 . As shown in Figure 1B, isochlorogenic acid C and chelerythrine chloride exhibited greater inhibitory potency with IC 50 values lower than that of the positive control.…”

Coptisine fromCoptis chinensisexerts diverse beneficial properties: A concise review

“…Similarly, coptisine (50 μmol/L, 0‐120s) was revealed to reduce S.aureus adhesion and inhibit PfDHODH, an anti‐malarial chemotherapy target . Coptisine (50‐200 μmol/L, 30 minutes) also exhibits anti‐H.pylori effect through the inhibition of urease activity, suggesting coptisine was a promising drug for digestive diseases . Moreover, Zhang et al built a nude mouse model of chemotherapy‐related diarrhoea by using irinotecan, and the result showed coptisine (30 mg/kg, oral, twice a day, 4 days) was able to reduce the degree of diarrhoea and ileum mucosal injury through modulating IκBα/NF‐κB signalling pathway .…”

UPLC-Q-TOF/MS-Based Serum and Urine Metabonomics Study on the Ameliorative Effects of Palmatine on Helicobacter pylori–Induced Chronic Atrophic Gastritis

“…It can be used to relieve bacterial dysentery, gynecological inflammation and urinary tract-related surgical infections on clinic ( Yokozawa et al., 2005 ; Wang et al., 2017 ). It has been the subject of scientific interest in recent years due to its multiple antibacterial, antiviral, and gastrointestinal protection biological activities ( Li et al., 2018 ; Chen et al., 2020 ). However, the largely potential anti-gastritis mechanism of Pal remain unknown, and whether Pal can be safely and effectively used in clinical still needs more investigation.…”