title: Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis.
abstract: The Erm family of methyltransferases confers resistance to the macrolide-lincosamide-streptogramin type B (MLS) antibiotics through the methylation of 23S ribosomal RNA. Upon the methylation of RNA, the MLS antibiotics lose their ability to bind to the ribosome and exhibit their antibiotic activity. Using an NMR-based screen, we identified a series of triazine-containing compounds that bind weakly to ErmAM. These initial lead compounds were optimized by the parallel synthesis of a large number of analogues, resulting in compounds which inhibit the Erm-mediated methylation of rRNA in the low micromolar range. NMR and X-ray structures of enzyme/inhibitor complexes reveal that the inhibitors bind to the S-adenosylmethionine binding site on the Erm protein. These compounds represent novel methyltransferase inhibitors that serve as new leads for the reversal of Erm-mediated MLS antibiotic resistance.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: J
authors.initials: J
authors.lastname: Dinges
authors.forename: J M
authors.initials: JM
authors.lastname: Schkeryantz
authors.forename: D
authors.initials: D
authors.lastname: Janowick
authors.forename: M
authors.initials: M
authors.lastname: Kaminski
authors.forename: M
authors.initials: M
authors.lastname: Tufano
authors.forename: D J
authors.initials: DJ
authors.lastname: Augeri
authors.forename: A
authors.initials: A
authors.lastname: Petros
authors.forename: V
authors.initials: V
authors.lastname: Nienaber
authors.forename: P
authors.initials: P
authors.lastname: Zhong
authors.forename: R
authors.initials: R
authors.lastname: Hammond
authors.forename: M
authors.initials: M
authors.lastname: Coen
authors.forename: B
authors.initials: B
authors.lastname: Beutel
authors.forename: L
authors.initials: L
authors.lastname: Katz
authors.forename: S W
authors.initials: SW
authors.lastname: Fesik
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004352:Drug Resistance, Microbial; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D008958:Models, Molecular; D011487:Protein Conformation; D012436:S-Adenosylmethionine / Q000378:metabolism; D013329:Structure-Activity Relationship; D014227:Triazines
chemical_list: D008024:Ligands; D014227:Triazines; D012436:S-Adenosylmethionine; D008780:Methyltransferases; C035181:rRNA (adenosine-O-2'-)methyltransferase