title: Structure-Based Identification of a Potent Inhibitor Targeting Stp1-Mediated Virulence Regulation in Staphylococcus aureus.
abstract: The increasing threats of antibiotic resistance urge the need for developing new strategies against bacterial infections. Targeting eukaryotic-like Ser/Thr phosphatase Stp1-mediated virulence regulation represents a promising approach for combating staphylococcal infection yet to be explored. Here, we report the 2.32-Å resolution crystal structure of Stp1. Stp1 binds an unexpected fourth metal ion, which is important for Stp1's enzymatic activity as demonstrated by amino acid substitution studies. Inspired by the structural details of Stp1, we identified a potent and selective Stp1 inhibitor, aurintricarboxylic acid (ATA). Transcriptome analysis and biochemical studies supported Stp1 as the target of ATA inhibition within the pathogen, preventing upregulation of virulence genes. Notably, ATA did not affect in vitro growth of Staphylococcus aureus, while simultaneously attenuating staphylococcal virulence in mice. Our findings demonstrate that ATA is a potent anti-virulence compound against staphylococcal infection, laying the foundation for further developing new scaffolds for Stp1-targeted small molecules.
authors: Key Lab of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
authors: Weihao
authors: W
authors: Zheng
authors: Key Lab of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
authors: Xiaodan
authors: X
authors: Cai
authors: Key Lab of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
authors: Mingsheng
authors: M
authors: Xie
authors: Key Lab of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China.
authors: Yujie
authors: Y
authors: Liang
authors: Department of Biology, South University of Science and Technology of China, Shenzhen 518055, China; SZCDC-SUSTech Joint Key Laboratory for Tropical Diseases, Shenzhen Center for Disease Control and Prevention, Shenzhen, 518055, China. Electronic address: wangtao@sustc.edu.cn.
authors: Tao
authors: T
authors: Wang
authors: Key Lab of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen 518055, China. Electronic address: lizg@pkusz.edu.cn.
authors: Zigang
authors: Z
authors: Li
mesh_terms: D000818:Animals; D001312:Aurintricarboxylic Acid / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity*; D013329:Structure-Activity Relationship; D014774:Virulence / Q000187:drug effects
chemical_list: D001312:Aurintricarboxylic Acid; D010744:Phosphoric Monoester Hydrolases