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bioRxiv · 10.1101/2021.07.30.454469

Directed biosynthesis of fluorinated polyketides

Rittner, A.·Joppe, M.·Schmidt, J. J.·Mayer, L. M.·Heid, E.·Sherman, D. H.·Grininger, M.
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Abstract

Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-specific incorporation of fluorine in complex molecules have improved in recent years, approaches for the direct biosynthetic fluorination of natural compounds are still rare. Herein, we present a broadly applicable approach for site-specific, biocatalytic derivatization of polyketides with fluorine. Specifically, we exchanged the native acyltransferase domain (AT) of a polyketide synthase (PKS), which acts as the gatekeeper for selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase (FAS). The resulting PKS/FAS hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl disubstitutions in polyketide scaffolds. Addition of a fluorine atom is often a decisive factor toward developing superior properties in next-generation antibiotics, including the macrolide solithromycin. We demonstrate the feasibility of our approach in the semisynthesis of a fluorinated derivative of the macrolide antibiotic YC-17.

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Rittner, A., Joppe, M., Schmidt, J. J., Mayer, L. M., Heid, E., Sherman, D. H., Grininger, M.. 2021-07-30. Directed biosynthesis of fluorinated polyketides. https://doi.org/10.1101/2021.07.30.454469

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