Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics

• Published in: Angewandte Chemie International Edition Vol. 59; no. 20; pp. 7871 - 7880
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 11.05.2020; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - metabolism; Anti-Bacterial Agents - pharmacology; Antibiotics; Atopic dermatitis; Autoimmunity - drug effects; Biotransformation; Chemistry; Chemistry, Multidisciplinary; Colitis; Cyclopropane; Dermatitis; Dimers; Drug metabolism; Drug resistance; Immunologic Factors - chemistry; Immunologic Factors - metabolism; Immunologic Factors - pharmacology; Immunomodulators; inflammation; Inflammatory bowel diseases; Intestine; Metabolism; Methicillin; Mice; microbiome; natural products; Photorhabdus; Photorhabdus - metabolism; Physical Sciences; Psoriasis; Resorcinols - chemistry; Resorcinols - metabolism; Resorcinols - pharmacology; Science & Technology; Signs and symptoms; Skin diseases; Staphylococcus aureus; Stilbene; stilbenes; Stilbenes - chemistry; Stilbenes - metabolism; Stilbenes - pharmacology; Structure-function relationships; Vancomycin; stilbenes; OXIDATIVE STRESS; EFFICACY; SAFETY; ASYMBIOTICA; STILBENE PHYTOALEXINS; INSECT; IDENTIFICATION; microbiome; natural products; inflammation; ARYL-HYDROCARBON RECEPTOR; TOPICAL WBI-1001; antibiotics; PHOTORHABDUS-LUMINESCENS
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.201916204

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. Antimicrobials on tap: The stilbene tapinarof, a drug used to treat inflammatory skin diseases, is transformed into two novel dimers in Photorhabdus. A cupin enzyme contributes to the oxidative dimerization of tapinarof and other dietary stilbenes. While tapinarof significantly reduces severe colitis symptoms in a mouse model, the dimers display antimicrobial activity against Mycobacterium and the antibiotic‐resistant pathogens MRSA and VRE.