title: Multistep virtual screening for rapid and efficient identification of non-nucleoside bacterial thymidine kinase inhibitors.
abstract: Antimicrobial activity of trimethoprim/sulfamethoxazole (SXT) against Staphylococcus aureus (S. aureus) is antagonized by thymidine, which is abundant in infected or inflamed human tissue. To restore the antimicrobial activity of SXT in the presence of thymidine, we screened for small-molecule inhibitors of S. aureus thymidine kinase with non-nucleoside scaffolds. We present the successful application of an adaptive virtual screening protocol for novel antibiotics using a combination of ligand- and structure-based approaches. Two consecutive rounds of virtual screening and in vitro testing were performed that resulted in several non-nucleoside hits. The most potent compound exhibits substantial antimicrobial activity against both methicillin-resistant S. aureus strain ATCC 700699 and nonresistant strain ATCC 29213, when combined with SXT in the presence of thymidine. This study demonstrates how virtual screening can be used to guide hit finding in antibacterial screening campaigns with minimal experimental effort.
authors.affiliation: Institute of Medical Microbiology and Infection Control, Hospital of Goethe-University, Paul-Ehrlich-Strasse 40, 60596 Frankfurt/Main, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zander
authors.forename: Markus
authors.initials: M
authors.lastname: Hartenfeller
authors.forename: Volker
authors.initials: V
authors.lastname: Hähnke
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.forename: Silke
authors.initials: S
authors.lastname: Besier
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Wichelhaus
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000595:Amino Acid Sequence; D015195:Drug Design; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016415:Sequence Alignment; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors*; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D013937:Thymidine Kinase