Precursor Directed Biosynthesis of an Orthogonally Functional Erythromycin Analogue: Selectivity in the Ribosome Macrolide Binding Pocket

• Published in: Journal of the American Chemical Society Vol. 134; no. 29; pp. 12259 - 12265
• Main Authors: Harvey, Colin J. B, Puglisi, Joseph D, Pande, Vijay S, Cane, David E, Khosla, Chaitan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25.07.2012
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Bacillus subtilis - drug effects; Binding Sites; Erythromycin - chemistry; Erythromycin - metabolism; Erythromycin - pharmacology; Escherichia coli - genetics; Escherichia coli - metabolism; Industrial Microbiology - methods; Models, Molecular; Ribosomes - chemistry; Ribosomes - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja304682q

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.