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Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics
Author(s) -
Park Hyun Bong,
Goddard Tyler N.,
Oh Joonseok,
Patel Jaymin,
Wei Zheng,
Perez Corey E.,
Mercado Brandon Q.,
Wang Rurun,
Wyche Thomas P.,
Piizzi Grazia,
Flavell Richard A.,
Crawford Jason M.
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201916204
Subject(s) - photorhabdus , microbiology and biotechnology , staphylococcus aureus , enterococcus faecalis , antibiotics , bacteria , biology , chemistry , genetics
Tapinarof is a stilbene drug that is used to treat psoriasis and atopic dermatitis, and is thought to function through regulation of the AhR and Nrf2 signaling pathways, which have also been linked to inflammatory bowel diseases. It is produced by the gammaproteobacterial Photorhabdus genus, which thus represents a model to probe tapinarof structural and functional transformations. We show that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that a cupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers. One dimer has activity against methicillin‐resistant Staphylococcus aureus (MRSA) and vancomycin‐resistant Enterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to a cyclopropane‐bridge‐containing hexacyclic framework that exhibits activity against Mycobacterium . These dimers lack efficacy in a colitis mouse model, whereas the monomer reduces disease symptoms.