title: Precursor directed biosynthesis of an orthogonally functional erythromycin analogue: selectivity in the ribosome macrolide binding pocket.
abstract: The macrolide antibiotic erythromycin A and its semisynthetic analogues have been among the most useful antibacterial agents for the treatment of infectious diseases. Using a recently developed chemical genetic strategy for precursor-directed biosynthesis and colony bioassay of 6-deoxyerythromycin D analogues, we identified a new class of alkynyl- and alkenyl-substituted macrolides with activities comparable to that of the natural product. Further analysis revealed a marked and unexpected dependence of antibiotic activity on the size and degree of unsaturation of the precursor. Based on these leads, we also report the precursor-directed biosynthesis of 15-propargyl erythromycin A, a novel antibiotic that not only is as potent as erythromycin A with respect to its ability to inhibit bacterial growth and cell-free ribosomal protein biosynthesis but also harbors an orthogonal functional group that is capable of facile chemical modification.
authors: Department of Chemistry, Stanford University, Stanford, California 94305, USA.
authors: Colin J B
authors: CJ
authors: Harvey
authors: Joseph D
authors: JD
authors: Puglisi
authors: Vijay S
authors: VS
authors: Pande
authors: David E
authors: DE
authors: Cane
authors: Chaitan
authors: C
authors: Khosla
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001665:Binding Sites; D004917:Erythromycin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D007218:Industrial Microbiology / Q000379:methods; D008958:Models, Molecular; D012270:Ribosomes / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin