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

Bacterial Autoimmune Drug Metabolism Transforms an Immunomodulator into Structurally and Functionally Divergent Antibiotics. Angew Chem Int Ed Engl. 2020 Feb 25;: Authors: Park HB, Goddard TN, Oh J, Patel J, Wei Z, Perez CE, Mercado BQ, Wang R, Wyche TP, Piizzi G, Flavell RA, Crawford J Abstract 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. PMID: 32097515 [PubMed - as...
Source: Angewandte Chemie - Category: Chemistry Authors: Tags: Angew Chem Int Ed Engl Source Type: research