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Discovering the Microbial Enzymes Driving Drug Toxicity with Activity-Based Protein Profiling.

Jariwala PB, Pellock SJ, Goldfarb D, Cloer EW, Artola M, Simpson JB, Bhatt AP, Walton WG, Roberts LR, Major MB, Davies GJ, Overkleeft HS, Redinbo MR
ACS Chem Biol 15 217-225 (2020)
Cited: 35 times
EuropePMC logo PMID: 31774274

Abstract

It is increasingly clear that interindividual variability in human gut microbial composition contributes to differential drug responses. For example, gastrointestinal (GI) toxicity is not observed in all patients treated with the anticancer drug irinotecan, and it has been suggested that this variability is a result of differences in the types and levels of gut bacterial β-glucuronidases (GUSs). GUS enzymes promote drug toxicity by hydrolyzing the inactive drug-glucuronide conjugate back to the active drug, which damages the GI epithelium. Proteomics-based identification of the exact GUS enzymes responsible for drug reactivation from the complexity of the human microbiota has not been accomplished, however. Here, we discover the specific bacterial GUS enzymes that generate SN-38, the active and toxic metabolite of irinotecan, from human fecal samples using a unique activity-based protein profiling (ABPP) platform. We identify and quantify gut bacterial GUS enzymes from human feces with an ABPP-enabled proteomics pipeline and then integrate this information with ex vivo kinetics to pinpoint the specific GUS enzymes responsible for SN-38 reactivation. Furthermore, the same approach also reveals the molecular basis for differential gut bacterial GUS inhibition observed between human fecal samples. Taken together, this work provides an unprecedented technical and bioinformatics pipeline to discover the microbial enzymes responsible for specific reactions from the complexity of human feces. Identifying such microbial enzymes may lead to precision biomarkers and novel drug targets to advance the promise of personalized medicine.

Reviews - 6nzg mentioned but not cited (1)

  1. A New Paradigm in the Relationship between Gut Microbiota and Breast Cancer: β-glucuronidase Enzyme Identified as Potential Therapeutic Target. Fernández-Murga ML, Gil-Ortiz F, Serrano-García L, Llombart-Cussac A. Pathogens 12 1086 (2023)

Articles - 6nzg mentioned but not cited (1)

  1. Discovering the Microbial Enzymes Driving Drug Toxicity with Activity-Based Protein Profiling. Jariwala PB, Pellock SJ, Goldfarb D, Cloer EW, Artola M, Simpson JB, Bhatt AP, Walton WG, Roberts LR, Major MB, Davies GJ, Overkleeft HS, Redinbo MR. ACS Chem Biol 15 217-225 (2020)


Reviews citing this publication (18)

  1. Deconstructing Mechanisms of Diet-Microbiome-Immune Interactions. Alexander M, Turnbaugh PJ. Immunity 53 264-276 (2020)
  2. The Role of Gut Microbial β-Glucuronidase in Estrogen Reactivation and Breast Cancer. Sui Y, Wu J, Chen J. Front Cell Dev Biol 9 631552 (2021)
  3. Towards a mechanistic understanding of reciprocal drug-microbiome interactions. Zimmermann M, Patil KR, Typas A, Maier L. Mol Syst Biol 17 e10116 (2021)
  4. Plant Glycosides and Glycosidases: A Treasure-Trove for Therapeutics. Kytidou K, Artola M, Overkleeft HS, Aerts JMFG. Front Plant Sci 11 357 (2020)
  5. Relationship Between the Gut Microbiome and Systemic Chemotherapy. Ervin SM, Ramanan SV, Bhatt AP. Dig Dis Sci 65 874-884 (2020)
  6. Microbiota and Colorectal Cancer: From Gut to Bedside. Silva M, Brunner V, Tschurtschenthaler M. Front Pharmacol 12 760280 (2021)
  7. Contribution of the Gut Microbiome to Drug Disposition, Pharmacokinetic and Pharmacodynamic Variability. Tsunoda SM, Gonzales C, Jarmusch AK, Momper JD, Ma JD. Clin Pharmacokinet 60 971-984 (2021)
  8. Microbiota-Host-Irinotecan Axis: A New Insight Toward Irinotecan Chemotherapy. Yue B, Gao R, Wang Z, Dou W. Front Cell Infect Microbiol 11 710945 (2021)
  9. Methodological Advances to Study Contaminant Biotransformation: New Prospects for Understanding and Reducing Environmental Persistence? Fenner K, Elsner M, Lueders T, McLachlan MS, Wackett LP, Zimmermann M, Drewes JE. ACS ES T Water 1 1541-1554 (2021)
  10. Proteomics and Metaproteomics Add Functional, Taxonomic and Biomass Dimensions to Modeling the Ecosystem at the Mucosal-luminal Interface. Li L, Figeys D. Mol Cell Proteomics 19 1409-1417 (2020)
  11. A structural metagenomics pipeline for examining the gut microbiome. Walker ME, Simpson JB, Redinbo MR. Curr Opin Struct Biol 75 102416 (2022)
  12. Bacteria-Mediated Modulatory Strategies for Colorectal Cancer Treatment. Mueller AL, Brockmueller A, Fahimi N, Ghotbi T, Hashemi S, Sadri S, Khorshidi N, Kunnumakkara AB, Shakibaei M. Biomedicines 10 832 (2022)
  13. Activity-based probes in pathogenic bacteria: Investigating drug targets and molecule specificity. Lembke HK, Carlson EE. Curr Opin Chem Biol 76 102359 (2023)
  14. Activity-based protein profiling in microbes and the gut microbiome. Han L, Chang PV. Curr Opin Chem Biol 76 102351 (2023)
  15. Estrobolome and Hepatocellular Adenomas-Connecting the Dots of the Gut Microbial β-Glucuronidase Pathway as a Metabolic Link. Bucurica S, Lupanciuc M, Ionita-Radu F, Stefan I, Munteanu AE, Anghel D, Jinga M, Gaman EL. Int J Mol Sci 24 16034 (2023)
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  18. Using click chemistry to study microbial ecology and evolution. van Kasteren S, Rozen DE. ISME Commun 3 9 (2023)

Articles citing this publication (15)

  1. Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy. Bhatt AP, Pellock SJ, Biernat KA, Walton WG, Wallace BD, Creekmore BC, Letertre MM, Swann JR, Wilson ID, Roques JR, Darr DB, Bailey ST, Montgomery SA, Roach JM, Azcarate-Peril MA, Sartor RB, Gharaibeh RZ, Bultman SJ, Redinbo MR. Proc Natl Acad Sci U S A 117 7374-7381 (2020)
  2. Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis. Rizzo A, Nannini M, Novelli M, Dalia Ricci A, Scioscio VD, Pantaleo MA. Ther Adv Med Oncol 12 1758835920936932 (2020)
  3. Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract. Zhang J, Walker ME, Sanidad KZ, Zhang H, Liang Y, Zhao E, Chacon-Vargas K, Yeliseyev V, Parsonnet J, Haggerty TD, Wang G, Simpson JB, Jariwala PB, Beaty VV, Yang J, Yang H, Panigrahy A, Minter LM, Kim D, Gibbons JG, Liu L, Li Z, Xiao H, Borlandelli V, Overkleeft HS, Cloer EW, Major MB, Goldfarb D, Cai Z, Redinbo MR, Zhang G. Nat Commun 13 136 (2022)
  4. Quantitative Investigation of Irinotecan Metabolism, Transport, and Gut Microbiome Activation. Parvez MM, Basit A, Jariwala PB, Gáborik Z, Kis E, Heyward S, Redinbo MR, Prasad B. Drug Metab Dispos 49 683-693 (2021)
  5. Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes. Elmassry MM, Kim S, Busby B. PLoS One 16 e0244876 (2021)
  6. β-Glucuronidase Pattern Predicted From Gut Metagenomes Indicates Potentially Diversified Pharmacomicrobiomics. Candeliere F, Raimondi S, Ranieri R, Musmeci E, Zambon A, Amaretti A, Rossi M. Front Microbiol 13 826994 (2022)
  7. Quantitative Metaproteomics and Activity-based Protein Profiling of Patient Fecal Microbiome Identifies Host and Microbial Serine-type Endopeptidase Activity Associated With Ulcerative Colitis. Thuy-Boun PS, Wang AY, Crissien-Martinez A, Xu JH, Chatterjee S, Stupp GS, Su AI, Coyle WJ, Wolan DW. Mol Cell Proteomics 21 100197 (2022)
  8. Metagenomics combined with activity-based proteomics point to gut bacterial enzymes that reactivate mycophenolate. Simpson JB, Sekela JJ, Graboski AL, Borlandelli VB, Bivins MM, Barker NK, Sorgen AA, Mordant AL, Johnson RL, Bhatt AP, Fodor AA, Herring LE, Overkleeft H, Lee JR, Redinbo MR. Gut Microbes 14 2107289 (2022)
  9. Who Is Metabolizing What? Discovering Novel Biomolecules in the Microbiome and the Organisms Who Make Them. Couvillion SP, Agrawal N, Colby SM, Brandvold KR, Metz TO. Front Cell Infect Microbiol 10 388 (2020)
  10. Synthesis of broad-specificity activity-based probes for exo-β-mannosidases. McGregor NGS, Kuo CL, Beenakker TJM, Wong CS, Offen WA, Armstrong Z, Florea BI, Codée JDC, Overkleeft HS, Aerts JMFG, Davies GJ. Org Biomol Chem 20 877-886 (2022)
  11. Metabolically-targeted dCas9 expression in bacteria. Pellegrino GM, Browne TS, Sharath K, Bari KA, Vancuren SJ, Allen-Vercoe E, Gloor GB, Edgell DR. Nucleic Acids Res 51 982-996 (2023)
  12. Chemoproteomic Approaches for Unraveling Prokaryotic Biology. Malarney KP, Chang PV. Isr J Chem 63 e202200076 (2023)
  13. Dissecting the human gut microbiome to better decipher drug liability: A once-forgotten organ takes center stage. Cai J, Auster A, Cho S, Lai Z. J Adv Res 52 171-201 (2023)
  14. Diverse but desolate landscape of gut microbial azoreductases: A rationale for idiopathic IBD drug response. Simpson JB, Sekela JJ, Carry BS, Beaty V, Patel S, Redinbo MR. Gut Microbes 15 2203963 (2023)
  15. Microbial β-glucuronidases drive human periodontal disease etiology. Lietzan AD, Simpson JB, Walton WG, Jariwala PB, Xu Y, Boynton MH, Liu J, Redinbo MR. Sci Adv 9 eadg3390 (2023)


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