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Issue 11, 2017

Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering

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Abstract

Nonribosomal peptide synthetases represent potential platforms for the design and engineering of structurally complex peptides. While previous focus has been centred mainly on bacterial systems, fungal synthetases assembling drugs like the antifungal echinocandins, the antibacterial cephalosporins or the anthelmintic cyclodepsipeptide (CDP) PF1022 await in-depth exploitation. As various mechanistic features of fungal CDP biosynthesis are only partly understood, effective engineering of NRPSs has been severely hampered. By combining protein truncation, in trans expression and combinatorial swapping, we assigned important functional segments of fungal CDP synthetases and assessed their in vivo biosynthetic capabilities. Hence, artificial assembly line components comprising of up to three different synthetases were generated. Using Aspergillus niger as a heterologous expression host, we obtained new-to-nature octa-enniatin (4 mg L−1) and octa-beauvericin (10.8 mg L−1), as well as high titers of the hybrid CDP hexa-bassianolide (1.3 g L−1) with an engineered ring size. The hybrid compounds showed up to 12-fold enhanced antiparasitic activity against Leishmania donovani and Trypanosoma cruzi compared to the reference drugs miltefosine and benznidazole, respectively. Our findings thus contribute to a rational engineering of iterative nonribosomal assembly lines.

Graphical abstract: Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering

Supplementary files

Article information


Submitted
14 Jul 2017
Accepted
25 Sep 2017
First published
25 Sep 2017

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2017,8, 7834-7843
Article type
Edge Article

Harnessing fungal nonribosomal cyclodepsipeptide synthetases for mechanistic insights and tailored engineering

C. Steiniger, S. Hoffmann, A. Mainz, M. Kaiser, K. Voigt, V. Meyer and R. D. Süssmuth, Chem. Sci., 2017, 8, 7834 DOI: 10.1039/C7SC03093B

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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