Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs

Dvořák, Zdeněk; Klapholz, Max; Burris, Thomas P.; Willing, Benjamin P.; Gioiello, Antimo; Pellicciari, Roberto; Galli, Francesco; March, John C.; O’Keefe, Stephen J.; Sartor, R. Balfour; Kim, Chang H.; Levy, Maayan; Mani, Sridhar

doi:10.1124/molpharm.120.000035

Cited by 8 publications

(8 citation statements)

References 116 publications

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“…In addition to xenobiotic ligands, several endogenous and microbially produced AhR ligands have been identified so far. Of note, microbial metabolites have been considered to be a treasure trove for using biomimicry to discover and optimize drugs . Indeed, we have recently demonstrated a concept of targeting PXR with novel compounds designed as tryptophan metabolite mimicry…”

Section: Discussionmentioning

confidence: 99%

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Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

et al. 2022

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Targeting the aryl hydrocarbon receptor (AhR) is an emerging therapeutic strategy for multiple diseases (e.g., inflammatory bowel disease). Thermosporothrix hazakensis microbial metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is a putative AhR endogenous ligand. To improve the chemical stability, we synthesized a series of ITE chemical mimics. Using a series of in vitro assays, we identified 2-(1H-indole-3-carbonyl)-N-methyl thiazole-4-carboxamide (ITE-CONHCH3) as a highly potent (EC50 = 1.6 nM) AhR agonist with high affinity (K i = 88 nM). ITE-CONHCH3 triggered AhR nuclear translocation and dimerization of AhR-ARNT, enhanced AhR binding in the CYP1A1 promoter, and induced AhR-regulated genes in an AhR-dependent manner. The metabolic stability of ITE-CONHCH3 in a cell culture was 10 times higher than that of ITE. Finally, we observed protective effects of ITE-CONHCH3 in mice with DSS-induced colitis. Overall, we demonstrate and validate a concept of microbial metabolite mimicry in the therapeutic targeting of AhR.

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Section: Discussionmentioning

confidence: 99%

“…On the basis of our previously proposed concept of developing potent ligands and potential drugs via microbial metabolite mimicry, ,, we attempted to develop ITE analogues to define potent and stable AhR agonists. We also performed an initial screen of the therapeutic validity of our ITE analogue in mice with intestinal inflammation.…”

Section: Introductionmentioning

confidence: 99%

Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

et al. 2022

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“…Microbial indole metabolite biomimicry has been successful for receptors beyond PXR (Dvorak, Klapholz et al 2020 has discovered complementary host targets of IPA, which further asserts the premise that IPA inhibits inflammation. In this context, indole acts to mitigate cytotoxicity by Klebsiella spp.…”

Section: Brief Historical Perspectivementioning

confidence: 93%

“…For example, indoles derived from the tryptophan metabolism are efficient AHR ligands (Rothhammer, Mascanfroni et al 2016). The indole scaffold is a promising chemical moiety for drug mimicry (Dvorak, Klapholz et al 2020). This scaffold is built on the observation that the microbial metabolite, indole, and its metabolites, are endogenous AHR ligands (Hubbard, Murray et al 2015, Lamas, Richard et al 2016.…”

Section: Key Recent Advancesmentioning

confidence: 99%

“…The goal of this minireview is to update new findings of microbial metabolite-nuclear receptor interactions with an emphasis on intestinal physiology, (Guan, Zhang et al 2021), and with this knowledge, demonstrate recent advances in developing potent microbial metabolite mimics as potential drugs of the future (Nuzzo and Brown 2020). It is essential to point out that the authors have previously published reviews on this topic (Dvorak, Klapholz et al 2020, Dvořák, Poulíková et al 2021; however, here, we will only provide new updates to this field of research .…”

Section: Introductionmentioning

confidence: 99%

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

Dvořák

Mani

2022

Drug Metab Dispos

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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.

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Exploring the Potential of Microbial Biomolecules in Advancing Human Health and Environmental Sustainability

Goel,

Choudhary,

Pattanaik

et al. 2024

Industrial Microbiology and Biotechnology

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Weak Microbial Metabolites: a Treasure Trove for Using Biomimicry to Discover and Optimize Drugs

Cited by 8 publications

References 116 publications

Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

Targeting the Aryl Hydrocarbon Receptor with Microbial Metabolite Mimics Alleviates Experimental Colitis in Mice

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

Exploring the Potential of Microbial Biomolecules in Advancing Human Health and Environmental Sustainability

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