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.
MeSH terms
-
Adenosine / metabolism
-
Amines / chemical synthesis
-
Amines / chemistry
-
Amines / metabolism
-
Amines / pharmacology
-
Anti-Bacterial Agents / chemical synthesis
-
Anti-Bacterial Agents / chemistry
-
Anti-Bacterial Agents / metabolism
-
Anti-Bacterial Agents / pharmacology*
-
Drug Evaluation, Preclinical
-
Enzyme Inhibitors / chemical synthesis
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / metabolism
-
Enzyme Inhibitors / pharmacology*
-
Haemophilus influenzae / drug effects
-
Haemophilus influenzae / enzymology*
-
Humans
-
Methionine / metabolism
-
Microbial Sensitivity Tests
-
Models, Molecular
-
Protein Structure, Tertiary
-
RNA, Transfer / chemistry
-
RNA, Transfer / metabolism
-
Structure-Activity Relationship
-
Substrate Specificity
-
tRNA Methyltransferases / antagonists & inhibitors*
-
tRNA Methyltransferases / chemistry
-
tRNA Methyltransferases / metabolism
Substances
-
Amines
-
Anti-Bacterial Agents
-
Enzyme Inhibitors
-
RNA, Transfer
-
Methionine
-
tRNA Methyltransferases
-
Adenosine
Associated data
-
PDB/4MCB
-
PDB/4MCC
-
PDB/4MCD