7-Deazaguanine modifications protect phage DNA from host restriction systems.

Genome modifications are central components of the continuous arms race between viruses and their hosts. The archaeosine base (G), which was thought to be found only in archaeal tRNAs, was recently detected in genomic DNA of Enterobacteria phage 9g and was proposed to protect phage DNA from a wide variety of restriction enzymes. In this study, we identify three additional 2'-deoxy-7-deazaguanine modifications, which are all intermediates of the same pathway, in viruses: 2'-deoxy-7-amido-7-deazaguanine (dADG), 2'-deoxy-7-cyano-7-deazaguanine (dPreQ) and 2'-deoxy-7- aminomethyl-7-deazaguanine (dPreQ).

Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism.

Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(NG37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from and , we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding.