We are alleviating the toxicity of the anticancer drug CPT-11 by modulating components of the GI microbiome. CPT-11 is essential in treating colorectal and pancreatic cancer, but dose-limiting toxicity severely reduces its efficacy. This toxicity is caused by a bacterial enzyme in enteric microbial symbiotes. The enzyme, beta glucuronidase, removes the inactivating glucuronic acid sugar from CPT-11's key metabolite, which reactivates the drug in the GI and produces epithelial cell death and acute diarrhea. We hypothesized that the selective, non-lethal inhibition of microbial beta glucuronidases would alleviate this side effect. This hypothesis tested true in proof-of-concept molecular-to-animal studies conducted in the previous project period. We will now advance the project in three crucial ways. First, we will characterize the range of active ?-glucuronidases present in the GI microbiome using structural biology and biochemistry. Second, we will create differentially optimized bacterial beta glucuronidase inhibitors via structural and chemical biology. Third, using deep-sequencing and metagenomics, we will unravel how this approach impacts the composition and activity of the GI microbiome. In summary, we seek to advance a novel paradigm - inhibiting specific microbial enzymes for therapeutic gain without harming the bacterial symbiotes essential for human health.

Public Health Relevance

We are alleviating the toxicity of the anticancer drug CPT-11 by modulating components of the GI microbiome. The results will reveal fundamental aspects of mammalian-microbial symbiosis and improve cancer chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA098468-11A1
Application #
8817985
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Fu, Yali
Project Start
2014-09-23
Project End
2019-08-31
Budget Start
2014-09-23
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$263,899
Indirect Cost
$88,633
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Pellock, Samuel J; Walton, William G; Biernat, Kristen A et al. (2018) Three structurally and functionally distinct ?-glucuronidases from the human gut microbe Bacteroides uniformis. J Biol Chem 293:18559-18573
Bhatt, Aadra P; Gunasekara, Dulan B; Speer, Jennifer et al. (2018) Nonsteroidal Anti-Inflammatory Drug-Induced Leaky Gut Modeled Using Polarized Monolayers of Primary Human Intestinal Epithelial Cells. ACS Infect Dis 4:46-52
Pellock, Samuel J; Creekmore, Benjamin C; Walton, William G et al. (2018) Gut Microbial ?-Glucuronidase Inhibition via Catalytic Cycle Interception. ACS Cent Sci 4:868-879
Yu, Ai-Ming; Ingelman-Sundberg, Magnus; Cherrington, Nathan J et al. (2017) Regulation of drug metabolism and toxicity by multiple factors of genetics, epigenetics, lncRNAs, gut microbiota, and diseases: a meeting report of the 21st International Symposium on Microsomes and Drug Oxidations (MDO). Acta Pharm Sin B 7:241-248
Bhatt, Aadra P; Redinbo, Matthew R; Bultman, Scott J (2017) The role of the microbiome in cancer development and therapy. CA Cancer J Clin 67:326-344
Pollet, Rebecca M; D'Agostino, Emma H; Walton, William G et al. (2017) An Atlas of ?-Glucuronidases in the Human Intestinal Microbiome. Structure 25:967-977.e5
Pellock, Samuel J; Redinbo, Matthew R (2017) Glucuronides in the gut: Sugar-driven symbioses between microbe and host. J Biol Chem 292:8569-8576
Redinbo, Matthew R (2017) Microbial Molecules from the Multitudes within Us. Cell Metab 25:230-232
Ghodge, Swapnil V; Biernat, Kristen A; Bassett, Sarah Jane et al. (2016) Post-translational Claisen Condensation and Decarboxylation en Route to the Bicyclic Core of Pantocin A. J Am Chem Soc 138:5487-90
Wierdl, Monika; Tsurkan, Lyudmila; Hatfield, M Jason et al. (2016) Tumour-selective targeting of drug metabolizing enzymes to treat metastatic cancer. Br J Pharmacol 173:2811-8

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