During the past few years, both the RNA triphosphatase and the RNA (guanine-N7) methyltransferase (N7-MTase) components of the RNA capping machinery have been major targets for the development of drugs directed against RNA cap synthesis [11, 12, 13, 14, 15, 16, 17, 18, 19, 20] . Of all the enzymes involved in RNA capping, the RNA guanylyltransferase (GTase) has traditionally been considered a poor candidate as an anti-microbial target because of the high mechanistic and structural conservation of this enzyme across species [21] . Based on various crystal structures of GTases, a general mechanism for phosphoryltransfer has previously been elucidated which involves conformational changes between an open and closed form of the enzyme [22, 23] . In the first step of the reaction, GTP binds to the open form of the enzyme which promotes closure of the Nterminal nucleotidyl transferase (NT) domain and the C-terminal oligomer-binding (OB) fold domain. This closure is stabilized by interactions between the residues of the NT domain, the bound nucleotide, and residues on the OB fold domain. Domain closure is then followed by hydrolysis of the GTP substrate to produce the enzyme-GMP covalent intermediate. Hydrolysis of GTP disrupts the interactions between the bound guanylate and the C-terminal OB fold domain, thus destabilizing the closed form of the enzyme, which opens up with the concomitant release of pyrophosphate. This exposes the RNA-binding site of the enzyme, thereby allowing the subsequent transfer of the GMP moiety onto the acceptor RNA. Figure 1 summarizes the mechanistic and structural pathway used by GTases.