Novel inhibitors of Erm methyltransferases from NMR and parallel synthesis

The Erm family of methyltransferases confers resistance to the macrolide-li ncosamide-streptogramin type B (MLS) antibiotics through the methylation of 23S ribosomal RNA. Upon the methylation of RNA, the MLS antibiotics lose t heir ability to bind to the ribosome and exhibit their antibiotic activity. Using an NMR-based screen, we identified a series of triazine-containing c ompounds that bind weakly to ErmAM. These initial lead compounds were optim ized by the parallel synthesis of a large number of analogues, resulting in compounds which inhibit the Erm-mediated methylation of rRNA in the low mi cromolar range. NMR and X-ray structures of enzyme/inhibitor complexes reve al that the inhibitors bind to the S-adenosylmethionine binding site on the Erm protein. These compounds represent novel methyltransferase inhibitors that serve as new leads for the reversal of Erm-mediated MLS antibiotic res istance.