Understanding the mechanism of macrolide antibiotic glycosylation
Prof Harry Gilbert
Dr David Bolam
Macrolides constitute an important group of antibiotics that target primarily gram-positive prokaryotes and collectively have been classed as the “last line of defence” against rapidly emerging pathogenic strains. Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, OleI and OleD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme-ligand complexes, in tandem with kinetic analysis of site-directed variants, provides insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OleD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin when bound to OleD and OleI, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. These data provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling.
Yang M, Proctor MR, Bolam DN, Errey JC, Field RA, Gilbert HJ and Davis BG. 2005. Journal of the American Chemical Society127, 9336-9337.
Bolam DN, Roberts S, Proctor MR, Turkenburg JP, Dodson EJ, Martinez-Fleites C, Yang M, Davis BG, Davies GJ and Gilbert HJ. 2007. Proc. Natl. Acad. Sci., USA. 104, 5336-5341.
