Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception

Pellock, S.J.; Creekmore, Benjamin C.; Walton, William G.; Mehta, Naimee; Biernat, Kristen A.; Cesmat, Andrew P.; Ariyarathna, Yamuna; Dunn, Zachary D.; Li, Bo; Jin, Jian; James, Lindsey I.; Redinbo, Matthew R.

doi:10.1021/acscentsci.8b00239

Cited by 58 publications

(81 citation statements)

References 33 publications

(92 reference statements)

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“…This difference in duration of exposure, and the observation in mice that the increase in GUS gene expression and enzyme activity appears to be relatively transient, suggest that serial samples from humans after the introduction of MMF will be very useful in evaluating our proposed mechanism of MMF toxicity. Lastly, while our data suggest that vancomycin can attenuate the MMF toxicity by targeting GUS-expressing bacteria, the non-specific devastation of the gut microbiome suggests that an alternative approach using specific GUS inhibitors may be a more effective therapeutic modality (49).…”

Section: Assessment Of Bacterial Gus Activity In Vivomentioning

confidence: 80%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has proven advantages over other immunosuppressive drugs but gastrointestinal (GI) side effects frequently limit its use. The pathways involved in the metabolism of the prodrug MMF and the bioactive derivative mycophenolic acid (MPA) are well characterized but the mechanism responsible for toxicity is unknown. Here we extend our previous observation that an intact gut microbiome is required for MMF-induced toxicity and demonstrate that gut bacterial metabolism is responsible for the GI inflammation and weight loss associated with MMF exposure. In mice consuming MMF, the introduction of vancomycin alone was sufficient to prevent or reverse MMF-induced weight loss and colonic inflammation. MMF induced the expansion of bacteria expressing b-glucuronidase (GUS) in the cecum and proximal colon. GUS activity, which is responsible for the catabolism of glucuronidated MPA (MPAG) to free MPA, was increased in the presence of MMF and eliminated by vancomycin. Vancomycin eliminated multiple Bacteroides spp. that flourished in the presence of MMF and prevented the breakdown of MPAG without negatively affecting serum MPA levels. Human data suggests that increased stool GUS activity can be associated with MMF-related toxicity. Our work provides a mechanism for the GI toxicity associated with MMF and a future direction for the development of therapeutics.3

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Section: Assessment Of Bacterial Gus Activity In Vivomentioning

confidence: 80%

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Taylor

Flannigan

Rahim

et al. 2019

Preprint

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“…Inhibition. The hundreds of unique gut microbial GUS enzymes mapped to date have been categorized into six functionally distinct groups based on active site architecture (13)(14)(15)(16)(17)(18)(19)(20). GUSs are encoded by Bacteroidetes, Firmicutes, and Proteobacteria; among these phyla, Proteobacteria are unique in encoding only Loop 1 (L1) GUS orthologs, which are most efficient with smaller glucuronidated substrates (14).…”

Section: Gus Loop Architecture Dictates Sn38-g Processing Efficiency Andmentioning

confidence: 99%

“…S1A), used in previous studies (8-11, 21, 22), and UNC10201652 (SI Appendix, Fig. S1B), a distinct mechanismbased GUS inhibitor that uniquely forms a covalent inhibitorglucuronide conjugate at the enzyme's active site (17). While UNC10201652 has been examined in vitro (17), the in vivo function is studied here.…”

Section: Gus Loop Architecture Dictates Sn38-g Processing Efficiency Andmentioning

confidence: 99%

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Bhatt

Pellock

Biernat

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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142

104

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Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immunedeficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage. microbiome | chemotherapy | cancer | gastrointestinal toxicity I rinotecan (CPT-11) is essential for treating colorectal and pancreatic cancers and is frequently administered as a mixture with 5-fluorouracil and/or oxaliplatin. Ongoing clinical trials seek to extend irinotecan to other forms of cancer. However, irinotecan causes both myelosuppression and gastrointestinal (GI) side effects, including mucositis and late-onset diarrhea, which are often dose limiting: 88% of irinotecan patients develop diarrhea, with 30% experiencing acute grade 3 to 4 diarrhea (1-3). This toxicity is frequently refractory to antimotility drugs. Thus, treating irinotecaninduced diarrhea is a significant clinical need (4, 5).The irinotecan prodrug is activated in vivo to SN38, a potent topoisomerase I inhibitor (6) that retards the growth of rapidly proliferating cells in tumors and the intestinal epithelium, which renews every 5 d. SN38 is detoxified through the addition of glucuronic acid (GlcA) to form SN38-G, a compound marked for elimination via the GI tract. Gut commensal bacterial β-glucuronidase (GUS) proteins remove GlcA from SN38-G. Reactivated SN38 inflicts epithelial damage, resulting in bleeding diarrhea and acute weight loss in animal models (7). We reduced irinotecan-induced gut toxicity using inhibitors that selectively, nonlethally, and potently block the actions of gut bacterial GUS enzymes (8,9). The utility of GUS inhibition also extends to drugs be...

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“…We have also included the only biomarker application of the enzyme filed within the period [256]. However, some of the patents and applications [257e263] emanated from published papers [19,210,228,229,241,262], reviewed in previous sections; therefore, only their summary is presented in Table 3.…”

Section: Patents Describing the Therapeutic Significance And Inhibitimentioning

confidence: 99%

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

Awolade

Cele

Kerru

et al. 2020

European Journal of Medicinal Chemistry

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BiomarkerEnzyme inhibition Molecular target Structure activity relationship a b s t r a c tThe emergence of disease and dearth of effective pharmacological agents on most therapeutic fronts, constitutes a major threat to global public health and man's existence. Consequently, this has created an exigency in the search for new drugs with improved clinical utility or means of potentiating available ones. To this end, accumulating empirical evidence supports molecular target therapy as a plausible egress and, b-glucuronidase (bGLU) e a lysosomal acid hydrolase responsible for the catalytic deconjugation of b-D-glucuronides has emerged as a viable molecular target for several therapeutic applications. The enzyme's activity level in body fluids is also deemed a potential biomarker for the diagnosis of some pathological conditions. Moreover, due to its role in colon carcinogenesis and certain drug-induced dose-limiting toxicities, the development of potent inhibitors of bGLU in human intestinal microbiota has aroused increased attention over the years. Nevertheless, although our literature survey revealed both natural products and synthetic scaffolds as potential inhibitors of the enzyme, only few of these have found clinical utility, albeit with moderate to poor pharmacokinetic profile. Hence, in this review we present a compendium of exploits in the present millennium directed towards the inhibition of bGLU. The aim is to proffer a platform on which new scaffolds can be modelled for improved bGLU inhibitory potency and the development of new therapeutic agents in consequential.

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Gut Microbial β-Glucuronidase Inhibition via Catalytic Cycle Interception

Cited by 58 publications

References 33 publications

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Vancomycin Relieves Mycophenolate Mofetil-Induced Gastrointestinal Toxicity by Eliminating Gut Bacterial β-Glucuronidase Activity

Targeted inhibition of gut bacterial β-glucuronidase activity enhances anticancer drug efficacy

Therapeutic significance of β-glucuronidase activity and its inhibitors: A review

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