Mazzei Luca, Wenzel Margot N, Cianci Michele, Palombo Marta, Casini Angela, Ciurli Stefano
Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, Viale Giuseppe Fanin 40, I-40127 Bologna, Italy.
School of Chemistry, Cardiff University, Main Building, Park Place, CF10 3AT Cardiff, United Kingdom.
ACS Med Chem Lett. 2019 Jan 4;10(4):564-570. doi: 10.1021/acsmedchemlett.8b00585. eCollection 2019 Apr 11.
The nickel-dependent enzyme urease is a virulence factor for a large number of critical human pathogens, making this enzyme a potential target of therapeutics for the treatment of resistant bacterial infections. In the search for novel urease inhibitors, five selected coordination and organometallic Au(III) compounds containing NN or CN and CNN ligands were tested for their inhibitory effects against (jack bean) urease. The results showed potent inhibition effects with IC values in the nanomolar range. The 2.14 Å resolution crystal structure of urease inhibited by the most effective Au(III) compound [Au(PbImMe)Cl]PF (PbImMe = 1-methyl-2-(pyridin-2-yl)-benzimidazole) reveals the presence of two Au ions bound to the conserved triad αCys322/αHis323/αMet367. The binding of the Au ions to these residues blocks the movement of a flap, located at the edge of the active site channel and essential for enzyme catalysis, completely obliterating the catalytic activity of urease. Overall, the obtained results constitute the basis for the design of new gold complexes as selective urease inhibitors with future antibacterial applications.
镍依赖性酶脲酶是许多重要人类病原体的毒力因子，这使得该酶成为治疗耐药细菌感染的潜在治疗靶点。在寻找新型脲酶抑制剂的过程中，测试了五种选定的含有NN或CN以及CNN配体的配位和有机金属金（III）化合物对刀豆脲酶的抑制作用。结果显示出强效的抑制作用，IC值在纳摩尔范围内。最有效的金（III）化合物[Au(PbImMe)Cl]PF（PbImMe = 1-甲基-2-(吡啶-2-基)-苯并咪唑）抑制的刀豆脲酶的2.14 Å分辨率晶体结构显示存在两个与保守三联体αCys322/αHis323/αMet367结合的金离子。金离子与这些残基的结合阻止了位于活性位点通道边缘且对酶催化至关重要的瓣的移动，完全消除了脲酶的催化活性。总体而言，所获得的结果为设计新型金配合物作为具有未来抗菌应用的选择性脲酶抑制剂奠定了基础。
