Pseudomonas aeruginosa is a leading cause of lethal, hospital-acquired infections. With up to 13% of these infections caused by multi-drug resistant bacteria, there is a need to develop new antibiotics against this pathogen. tRNA methyltransferase TrmD catalyzes the transfer of methyl group from S-adenosyl-L-methionine (SAM) to substrate tRNAs on the N1 atom of guanosine at position 37. This post-transcriptional modification on tRNA is required for the modulation of translation in bacteria, which makes trmD an essential protein for bacteria survival. Though several efforts had been made to develop competitive SAM inhibitors against TrmD activity, to date, no in silico methods has been employed to screen for such inhibitors. In this study, we have initiated a structure-based approach to develop novel inhibitors of TrmD. We first obtained crystal structures of TrmD at a resolution of 2.16 Å bound to S-adenosyl homocysteine and to the methyltransferase generic inhibitor, sinefungin (2.45 Å resolution). We then optimized these structures using several software algorithms including Prime protein refinement suite from Schrödinger. These optimization studies lay the necessary foundation for in silico screening for TrmD inhibitors using the Schrödinger Glide docking application with the 22 million-compound ZINC virtual compound library and further validation using molecular dynamics simulation.

Targeting tRNA methyltransferases for antibiotic development

251st National Meeting (2016)

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