Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics
| Autor: | Joonseok Oh, Richard A. Flavell, Zheng Wei, Brandon Q. Mercado, Rurun Wang, Thomas P. Wyche, Jaymin R. Patel, Grazia Piizzi, Hyun Bong Park, Corey E Perez, Jason M. Crawford, Tyler N. Goddard |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.drug_class
Antibiotics Autoimmunity 010402 general chemistry medicine.disease_cause 01 natural sciences Article Catalysis Enterococcus faecalis Microbiology Mice Stilbenes medicine Animals Immunologic Factors Biotransformation chemistry.chemical_classification biology 010405 organic chemistry Chemistry Resorcinols General Medicine General Chemistry biology.organism_classification Anti-Bacterial Agents 0104 chemical sciences Enzyme Staphylococcus aureus Photorhabdus Drug metabolism Bacteria Mycobacterium |
| Zdroj: | Angew Chem Int Ed Engl |
| ISSN: | 1521-3773 1433-7851 |
| Popis: | The stilbene tapinarof is a drug used to treat psoriasis and atopic dermatitis. Efficacy is thought to arise from its regulation of the aryl hydrocarbon receptor and nuclear factor erythroid 2-related factor 2 signaling pathways, which have also been linked to the severity of inflammatory bowel diseases. Tapinarof is produced by the gammaproteobacterial Photorhabdus genus, which infects insects and humans. Consequently, Photorhabdus represents a model to probe tapinarof structural and functional transformations. Here, we demonstrate that Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria. We show that a cupin contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers. One dimer has activity against MRSA and VRE, whereas another undergoes spontaneous cyclization events to construct a cyclopropane bridge-containing hexacyclic framework that exhibits activity against Mycobacterium. Consistent with the functional transformations, these dimers lack efficacy in a colitis mouse model, whereas the monomer reduces disease symptoms. |
| Databáze: | OpenAIRE |
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