The t-RNA-(N1G37) methyl transferase (TrmD) is essential for growth and conserved in both Gram-positive and Gram-negative bacterial pathogens. Since, in addition, TrmD is very distinct from its human ortholog TRM5, it is a suitable target for the design of novel antibacterials.  Screening of a small-molecule fragment collection using Haemophilus influenzae TrmD identified a series of compounds that were competitive with S-adenosyl methionine (SAM), the natural methyl donor. Guided by co-crystal structures, these fragments elaborated into a nanomolar inhibitor of a broad range of Gram-negative TrmD isozymes. This is the first report of nano-molar inhibitors of bacterial TrmD.

Structure-guided design of novel small molecule inhibitors of bacterial t-RNA-(N<sup>1</sup>G37)  methyl transferase (TrmD)

246th National Meeting (2013)

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Structure-guided design of novel small molecule inhibitors of bacterial t-RNA-(N1G37) methyl transferase (TrmD)

Structure-guided design of novel small molecule inhibitors of bacterial t-RNA-(N¹G37) methyl transferase (TrmD)