WITHDRAWN: Coptisine, an alkaloid from Rhizoma Coptidis, inhibits Helicobacter pylori urease activity by targeting its active site and maturation process

Abstract

// Cailan Li 1, * , Ping Huang 2, * , Kambo Wong 3 , Yifei Xu 2 , Lihua Tan 1 , Hanbin Chen 4 , Qiang Lu 5 , Chaodan Luo 1 , Chunlai Tam 3 , Lixiang Zhu 2 , Ziren Su 1, 6 and Jianhui Xie 7 1 Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China 2 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China 3 School of Life Sciences, Center for Protein Science and Crystallography, The Chinese University of Hong Kong, Hong Kong, P. R. China 4 The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China 5 Key Laboratory of Ministry of Education, Research Center of Chinese Herbal Resources and Engineering, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China 6 Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan, P. R. China 7 Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, P. R. China * These authors have contributed equally to this work Correspondence to: Ziren Su, email: suziren@gzucm.edu.cn Jianhui Xie, email: xiejianhui888@hotmail.com Keywords: coptisine; Helicobacter pylori urease; sulfhydryl group; nickel ion; UreG Received: May 18, 2017 Accepted: January 01, 2018 Published: January 02, 2018 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 MICs ranging from 25 to 50 μg/mL and MBCs 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 (JBU) was non-competitive. Importantly, coptisine also inhibited HPU by binding to its nickel metallocenter. 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.