Biomimetic synthesis and optimization of cyclic peptide antibiotics.
Molecules in nature are often brought to a bioactive conformation by ring formation (macrocyclization). A recurrent theme in the enzymatic synthesis of macrocyclic compounds by non-ribosomal and polyketide synthetases is the tethering of activated linear intermediates through thioester linkages to carrier proteins, in a natural analogy to solid-phase synthesis. A terminal thioesterase domain of the synthetase catalyses release from the tether and cyclization. Here we show that an isolated thioesterase can catalyse the cyclization of linear peptides immobilized on a solid-phase support modified with a biomimetic linker, offering the possibility of merging natural-product biosynthesis with combinatorial solid-phase chemistry. Starting from the cyclic decapeptide antibiotic tyrocidine A, this chemoenzymatic approach allows us to diversify the linear peptide both to probe the enzymology of the macrocyclizing enzyme, TycC thioesterase, and to create a library of cyclic peptide antibiotic products. We have used this method to reveal natural-product analogues of potential therapeutic utility; these compounds have an increased preference for bacterial over eukaryotic membranes and an improved spectrum of activity against some common bacterial pathogens.
Kohli
Rahul M
RM
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
Walsh
Christopher T
CT
Burkart
Michael D
MD
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D001688:Biological Products / Q000096:biosynthesis / Q000138:chemical synthesis / Q000494:pharmacology; D002384:Catalysis; D003500:Cyclization; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000494:pharmacology; D013379:Substrate Specificity; D013869:Thiolester Hydrolases / Q000378:metabolism; D014440:Tyrocidine / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000138:chemical synthesis / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001688:Biological Products; D010456:Peptides, Cyclic; D014440:Tyrocidine; D013869:Thiolester Hydrolases