title: Immobilization of a novel antibacterial agent on solid phase and subsequent isolation of EF-Tu.
abstract: Screening of our compound collection identified PNU-92560, a 2-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide, as a novel antibacterial agent. Extensive analogue development identified that the 2-position of the thiadiazole could be functionalized with a linker that would allow the compound to be attached to a solid support. The extreme insolubility of the analogues prevented the mechanism of action for these compounds to be determined utilizing traditional methodology. The solid-supported compounds were utilized as affinity columns to identify elongation factor Tu (EF-Tu) as a putative target for this class of compounds. The activity of the compounds in a metabolic labeling experiments and in translation assay supports the identity of the target for these compounds to be EF-Tu.
authors.affiliation: Pharmacia, Kalamazoo, Michigan 49001-0199, USA. mrdeibel@proteos.net
authors.forename: Martin R
authors.initials: MR
authors.lastname: Deibel
authors.forename: Alice L
authors.initials: AL
authors.lastname: Bodnar
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Yem
authors.forename: Cindy L
authors.initials: CL
authors.lastname: Wolfe
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Heckaman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bohanon
authors.forename: W Rodney
authors.initials: WR
authors.lastname: Mathews
authors.forename: Michael T
authors.initials: MT
authors.lastname: Sweeney
authors.forename: Gary E
authors.initials: GE
authors.lastname: Zurenko
authors.forename: Keith R
authors.initials: KR
authors.lastname: Marotti
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Boyle
authors.forename: Atli
authors.initials: A
authors.lastname: Thorarensen
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D016503:Drug Delivery Systems; D010444:Peptide Elongation Factor Tu / Q000302:isolation & purification* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C493147:2-(1,3,4)thiadiazolo(3,2-a)pyrimidine-6-carboxamide; D000900:Anti-Bacterial Agents; D011743:Pyrimidines; D013844:Thiazoles; D010444:Peptide Elongation Factor Tu