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Biomimetic synthesis and optimization of cyclic peptide antibiotics

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Abstract

Molecules in nature are often brought to a bioactive conformation by ring formation (macrocyclization)1. 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 synthesis2. A terminal thioesterase domain of the synthetase catalyses release from the tether and cyclization3,4. 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.

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Figure 1: Natural versus biomimetic macrocycle synthesis.
Figure 2: Improved analogues of tyrocidine A.

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Acknowledgements

We thank R. Kolter for providing strains for antibacterial assays, and the Harvard Center for Proteomics for access to equipment. We also thank M. D. Burke and J.-M. Gauguet for discussions. This work was supported by the NIH (C.T.W.). R.M.K. is supported by the Medical Scientist Training Program, and M.D.B. was an NIH post-doctoral fellow.

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Author notes

  1. Michael D. Burkart

    Present address: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093, USA

  2. Rahul M. Kohli and Michael D. Burkart: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 240 Longwood Avenue, Massachusetts, 02115, Boston, USA

    Rahul M. Kohli, Christopher T. Walsh & Michael D. Burkart

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  1. Rahul M. Kohli
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  2. Christopher T. Walsh
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Correspondence to Christopher T. Walsh.

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Kohli, R., Walsh, C. & Burkart, M. Biomimetic synthesis and optimization of cyclic peptide antibiotics. Nature 418, 658–661 (2002). https://doi.org/10.1038/nature00907

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