title: Experimentally validated novel inhibitors of Helicobacter pylori phosphopantetheine adenylyltransferase discovered by virtual high-throughput screening.
abstract: Helicobacter pylori is a major etiologic agent associated with the development and maintenance of human gastritis. The goal of this study was to develop novel antibiotics against H. pylori, and we thus targeted H. pylori phosphopantetheine adenylyltransferase (HpPPAT). PPAT catalyzes the penultimate step in coenzyme A biosynthesis. Its inactivation effectively prevents bacterial viability, making it an attractive target for antibacterial drug discovery. We employed virtual high-throughput screening and the HpPPAT crystal structure to identify compounds in the PubChem database that might act as inhibitors of HpPPAT. d-amethopterin is a potential inhibitor for blocking HpPPAT activity and suppressing H. pylori viability. Following treatment with d-amethopterin, H. pylori exhibited morphological characteristics associated with cell death. d-amethopterin is a mixed inhibitor of HpPPAT activity; it simultaneously occupies the HpPPAT 4'-phosphopantetheine- and ATP-binding sites. Its binding affinity is in the micromolar range, implying that it is sufficiently potent to serve as a lead compound in subsequent drug development. Characterization of the d-amethopterin and HpPPAT interaction network in a docked model will allow us to initiate rational drug optimization to improve the inhibitory efficacy of d-amethopterin. We anticipate that novel, potent, and selective HpPPAT inhibitors will emerge for the treatment of H. pylori infection.
authors.affiliation: Institute of Bioinformatics and Structural Biology and College of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chao-Sheng
authors.initials: CS
authors.lastname: Cheng
authors.forename: Kai-Fan
authors.initials: KF
authors.lastname: Jia
authors.forename: Ting
authors.initials: T
authors.lastname: Chen
authors.forename: Shun-Ya
authors.initials: SY
authors.lastname: Chang
authors.forename: Ming-Shen
authors.initials: MS
authors.lastname: Lin
authors.forename: Hsien-Sheng
authors.initials: HS
authors.lastname: Yin
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D003065:Coenzyme A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D062126:Databases, Chemical; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D057166:High-Throughput Screening Assays; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D010204:Pantetheine / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D010204:Pantetheine; D000255:Adenosine Triphosphate; D009713:Nucleotidyltransferases; C022315:pantetheine-phosphate adenylyltransferase; C003129:4'-phosphopantetheine; D003065:Coenzyme A; D008727:Methotrexate
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