1 research outputs found
Selective Inhibitors of Bacterial t‑RNA-(N<sup>1</sup>G37) Methyltransferase (TrmD) That Demonstrate Novel Ordering of the Lid Domain
The
tRNA-(N<sup>1</sup>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 <i>S</i>-adenosylmethionine (SAM), the physiological methyl donor
substrate. Guided by X-ray cocrystal structures, fragment <b>1</b> 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