UreG as a target for the development of urease inhibitor: a new strategy for design of antimicrobial agents

Abstract

Urease is a virulence factor found in many pathogenic bacteria e.g. Helicobacter pylori [1], and has attracted considerable attentions as a therapeutic target [2]. Unfortunately, development of urease inhibitors was not successful largely due to the fact that urease active site is deeply buried inside [3] and its substrate is high specific. Here, we demonstrate that, instead of directly targeting the active site of urease, the antiulcer drug colloidal bismuth subcitrate (CBS) inhibits urease activity through functional perturbation of a metallo-chaperon, UreG, a GTPase that plays a significant role towards the maturation of urease [4], as well as interferes with the formation of functional UreEUreG, UreG-UreFH complexes, thus disrupting urease maturation. Using UreG as a target via virtual screening, we subsequently experimentally validated several small molecules that are able to inhibit urease activity. We further demonstrate that these small molecules exhibit good inhibitory effect towards H. pylori even for antibiotic resistant strain. Our study strongly implicates metallochaperones involved in maturation of important microbial metalloenzymes as promising targets for the development of new class of antimicrobial agents. We thank RGC (17333616P&17305415P) and the University of Hong Kong for financial support. References [1] Mobley HLT, Island MD, Hausinger RP. Microbiol. Rev. 1995, 59, 451-480. [2] Follmer C. J. Clin. Pathol. 2010, 63, 424-430. [[3] Ha NC, Oh ST, Sung JY, et al Nat. Struct. Biol. 2001, 8, 505-509. [4] Yang X, Li H, Lai TP, Sun H. J. Biol. Chem. 2015, 290,12474-12485.