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

Abstract

Tapinarof is as tilbene drug that is used to treat psoriasis and atopic dermatitis,a nd 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,w hicht hus represents am odel to probe tapinarof structural and functional transformations.W es howt hat Photorhabdus transforms tapinarof into novel drug metabolism products that kill inflammatory bacteria, and that acupin enzyme contributes to the conversion of tapinarof and related dietary stilbenes into novel dimers.O ne dimer has activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistantE nterococcus faecalis (VRE), and another undergoes spontaneous cyclizations to ac yclopropane-bridge-containing hexacyclic framework that exhibits activity against Mycobacterium. These dimers lacke fficacy in ac olitis mouse model, whereas the monomer reduces disease symptoms.

First Use of Tapinarof Monotherapy for Seborrhoeic Dermatitis: A Case Report

“…It is currently unknown how exactly each AhR agonist may cause or ameliorate inflammation and remains a subject of intense study. Furthermore, incubation experiments of tapinarof with various microbe cultures suggest potential antimicrobial properties toward both fungi and gram-positive bacteria in an AhR-independent manner ( 14 ).…”

Tapinarof for the treatment of psoriasis

“…12,19 One such metabolite, 3,5-dihydroxy-4-isopropylstilbene (tapinarof), was isolated and identified. 12,21 Tapinarof binds directly to AhR, resulting in the suppression of inflammatory cytokines, the modulation of skin barrier protein expression, and antioxidant activity. 12,22 Tapinarof cream 1% (GSK-2894512) has the same active principle as benvitimod cream 1% (WBI-1001).…”

“…In fact, P. luminescens produces metabolites with antibacterial properties that responsible for the observed biological action 12,19 . One such metabolite, 3,5‐dihydroxy‐4‐isopropylstilbene (tapinarof), was isolated and identified 12,21 . Tapinarof binds directly to AhR, resulting in the suppression of inflammatory cytokines, the modulation of skin barrier protein expression, and antioxidant activity 12,22 …”

The AcrAB efflux pump confers self-resistance to stilbenes in Photorhabdus laumondii

“…The first step of ST biosynthesis in P. laumondii is catalyzed by a phenylalanine ammonia-lyase encoded by the nutrient limitation-induced stlA gene [5,13]. The two major STderivatives from Photorhabdus are 3,5-dihydroxy-4-isopropyl-trans-stilbene (IPS), also known as tapinarof [14], and 2-isopropyl-5-(3-phenyl-oxiranyl)-benzene-1,3-diol (ST epoxide), which derives from the epoxidation of the hydroxylated ST by a flavin adenine dinucleotide [15]. IPS has gained attention due to its multipotent action as an antibacterial, antifungal, antioxidant, insect innate immunosuppressor, and recently as a FDA approved anti-inflammatory/antimicrobial topical therapeutic agent (Tapinarof or benvitimod and sold under the brand name Vtama®) for the treatment of plaque psoriasis and atopic dermatitis [16].…”