title: Selective inhibitors of bacterial t-RNA-(N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain.
abstract: The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA.
authors: Departments of Chemistry, ‡Biosciences and §Discovery Sciences, Infection Innovative Medicines Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors: Pamela J
authors: PJ
authors: Hill
authors: Ayome
authors: A
authors: Abibi
authors: Robert
authors: R
authors: Albert
authors: Beth
authors: B
authors: Andrews
authors: Moriah M
authors: MM
authors: Gagnon
authors: Ning
authors: N
authors: Gao
authors: Tyler
authors: T
authors: Grebe
authors: Laurel I
authors: LI
authors: Hajec
authors: Jian
authors: J
authors: Huang
authors: Stephania
authors: S
authors: Livchak
authors: Sushmita D
authors: SD
authors: Lahiri
authors: David C
authors: DC
authors: McKinney
authors: Jason
authors: J
authors: Thresher
authors: Hongming
authors: H
authors: Wang
authors: Nelson
authors: N
authors: Olivier
authors: Ed T
authors: ET
authors: Buurman
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008715:Methionine / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D012343:RNA, Transfer / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D012359:tRNA Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000588:Amines; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D012343:RNA, Transfer; D008715:Methionine; D012359:tRNA Methyltransferases; D000241:Adenosine