title: Sulfonylpiperidines as novel, antibacterial inhibitors of Gram-positive thymidylate kinase (TMK).
abstract: Thymidylate kinase (TMK) is an essential enzyme for DNA synthesis in bacteria, phosphorylating deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), and thus is a potential new antibacterial drug target. Previously, we have described the first potent and selective inhibitors of Gram-positive TMK, leading to in vivo validation of the target. Here, a structure-guided design approach based on the initial series led to the discovery of novel sulfonylpiperidine inhibitors of TMK. Formation of hydrogen bonds with Arg48 in Staphylococcus aureus TMK was key to obtaining excellent enzyme affinity, as verified by protein crystallography. Replacement of a methylene linker in the series by a sulfonamide was accomplished with retention of binding conformation. Further optimization of logD yielded phenol derivative 11, a potent inhibitor of TMK showing excellent MICs against a broad spectrum of Gram-positive bacteria and >10(5) selectivity versus the human TMK homologue.
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, MA 02451, USA. gabriel@sagerx.com
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martínez-Botella
authors.forename: James T
authors.initials: JT
authors.lastname: Loch
authors.forename: Oluyinka M
authors.initials: OM
authors.lastname: Green
authors.forename: Sameer P
authors.initials: SP
authors.lastname: Kawatkar
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Olivier
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Keating
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010880:Piperidines; D013449:Sulfonamides; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase