title: Discovery of selective and potent inhibitors of gram-positive bacterial thymidylate kinase (TMK).
abstract: Thymidylate kinase (TMK) is an essential enzyme in bacterial DNA synthesis. The deoxythymidine monophosphate (dTMP) substrate binding pocket was targeted in a rational-design, structure-supported effort, yielding a unique series of antibacterial agents showing a novel, induced-fit binding mode. Lead optimization, aided by X-ray crystallography, led to picomolar inhibitors of both Streptococcus pneumoniae and Staphylococcus aureus TMK. MICs < 1 μg/mL were achieved against methicillin-resistant S. aureus (MRSA), S. pneumoniae, and vancomycin-resistant Enterococcus (VRE). Log D adjustments yielded single diastereomers 14 (TK-666) and 46, showing a broad antibacterial spectrum against Gram-positive bacteria and excellent selectivity against the human thymidylate kinase ortholog.
authors.affiliation: AstraZeneca Infection Innovative Medicines, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA. gabriel@sagerx.com
authors.forename: Gabriel
authors.initials: G
authors.lastname: Martínez-Botella
authors.forename: John N
authors.initials: JN
authors.lastname: Breen
authors.forename: James E S
authors.initials: JE
authors.lastname: Duffy
authors.forename: Jacques
authors.initials: J
authors.lastname: Dumas
authors.forename: Bolin
authors.initials: B
authors.lastname: Geng
authors.forename: Ian K
authors.initials: IK
authors.lastname: Gowers
authors.forename: Oluyinka M
authors.initials: OM
authors.lastname: Green
authors.forename: Satenig
authors.initials: S
authors.lastname: Guler
authors.forename: Martin F
authors.initials: MF
authors.lastname: Hentemann
authors.forename: Felix A
authors.initials: FA
authors.lastname: Hernandez-Juan
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: Sameer
authors.initials: S
authors.lastname: Kawatkar
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Larsen
authors.forename: Ovadia
authors.initials: O
authors.lastname: Lazari
authors.forename: James T
authors.initials: JT
authors.lastname: Loch
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Macritchie
authors.forename: Andrew R
authors.initials: AR
authors.lastname: McKenzie
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Newman
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Olivier
authors.forename: Linda G
authors.initials: LG
authors.lastname: Otterson
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Owens
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.forename: David W
authors.initials: DW
authors.lastname: Sheppard
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Keating
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D016983:Enterococcus / Q000187:drug effects*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D020713:Vancomycin Resistance / Q000187:drug effects*
chemical_list: C577953:2-(3-bromophenoxy)-4-(1-(3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)piperidin-1-yl)hexyl)benzoic acid; C577952:2-(3-bromophenoxy)-4-(3,3-dimethyl-1-((5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1-(2H)-yl)piperidin-1-yl)butyl)benzoic acid; D000900:Anti-Bacterial Agents; D001565:Benzoates; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013941:Thymine