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

Autor: Park HB; Department of Chemistry, Yale University, New Haven, CT, 06520, USA.; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA., Goddard TN; Department of Chemistry, Yale University, New Haven, CT, 06520, USA.; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA., Oh J; Department of Chemistry, Yale University, New Haven, CT, 06520, USA.; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA., Patel J; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA.; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT, 06520, USA., Wei Z; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA.; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA., Perez CE; Department of Chemistry, Yale University, New Haven, CT, 06520, USA.; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA., Mercado BQ; Department of Chemistry, Yale University, New Haven, CT, 06520, USA.; Chemical and Biophysical Instrumentation Center, Yale University, New Haven, CT, 06520, USA., Wang R; Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, USA., Wyche TP; Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, USA., Piizzi G; Exploratory Science Center, Merck & Co., Inc., Cambridge, MA, USA., Flavell RA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA.; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520, USA., Crawford JM; Department of Chemistry, Yale University, New Haven, CT, 06520, USA.; Chemical Biology Institute, Yale University, West Haven, CT, 06516, USA.; Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT, 06536, USA.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 May 11; Vol. 59 (20), pp. 7871-7880. Date of Electronic Publication: 2020 Mar 17.
DOI: 10.1002/anie.201916204
Abstrakt: 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.
(© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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