Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

Abstract

Xenobiotic receptors, for example like the pregnane X receptor, regulate multiple host physiological pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview will focus on recent efforts to derive potentially non-toxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic-receptor modifying pathophysiology. The review will include our perspective of the field and recommend certain directions for future research. SIGNIFICANCE STATEMENTThe xenobiotic receptors (XR) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors, but also to respond to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite-XR interactions and the translation of these findings towards discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.

Analysis of Human Gut Metabolites as Sources for the Design of Gut-Targeted Drugs

“…54 This has been followed by the development of the aryl hydrocarbon receptor, based on metabolite mimics too. 55,56 In addition, in other work a combined bioinformatic/cheminformatic analysis based on data from the Human Microbiome Project 15 has allowed to suggest several target-metabolite interactions that could be useful in drug discovery for inflammatory bowel disease. 57 Given all this background, the current work provides useful analyses that will help in the rational design of gut-targeted drugs based on (host or microbial) gut metabolites.…”

“…This similarity is in agreement with previous analyses that have stressed the structural similarity between systemic drugs and the corresponding metabolites, 33,34 as well as the above mentioned proof-of-concept examples of inhibitors of gut targets based on intestinal microbial metabolites. [54][55][56] This differential chemical class distribution has indeed been exploited in the case of two commercial drugs, orlistat and acarbose, which are in turn substrate analogs of two abundant sets of compounds in the gut, namely glycerolipids and oligosaccharides, rather unusual as source of systemic drugs.…”

In Vitro Safety Signals for Potential Clinical Development of the Anti-Inflammatory Pregnane X Receptor Agonist FKK6

“…FKK6 is a promising PXR-modulating candidate for locoregional rodent and human intestinal inflammation therapy. We have demonstrated previously that FKK6 is a modest PXR agonist ligand [12], and have argued for developing PXR modest agonists as potential new therapeutics for inflammatory bowel disease [8]. However, before proceeding with a preclinical development plan, we sought to clarify the basic in vitro pharmacologic properties of FKK6.…”

“…Zdeněk Dvořák 1,3,4,5,7,8,9,11,12,13 , Barbora Vyhlídalová 3,7,11 , Petra Pečinková 2,3,5 , Hao Li 2,3,5 , Pavel Anzenbacher 2,3,5,6,9,10,11 , Alena Špičáková 2,3,5,6 , Eva Anzenbacherová 2,3,5,6 , Vimanda Chow 2,3,5,6,10,11 , Jiabao Liu 2,3,5,6,10,11 , Henry Krause 2,3,5,6,10,11 , Derek Wilson 2,3,5,6,10,11 , Tibor Berés 2,3,5,6,10,11 , Petr Tarkowski 2,…”

“…However, more recently, multiple physiological roles of PXR have been unveiled, including regulating inappropriate inflammation in various organs like the gastrointestinal tract (e.g., inflammatory bowel disease; IBD) [1][2][3][4][5][6]. Since the initial discovery of the PXR and its functional importance as a master regulator of the drug metabolism [7], a new pharmacotherapeutic paradigm might be important in that, for specific diseases (e.g., IBD), dialing-in PXR activity, especially in the intestines and not systemically, could safely expand the new drug space [8,9]. Indeed, an example is the antibiotic rifaximin, which is used clinically in part for its PXR-agonist activity in treating inflammatory bowel disease [10].…”