Although non-pathogenic microbes that reside in our intestines generally provide us with numerous health and digestive benefits, a specific microfloral activity is also responsible for the severe and sometimes deadly gastrointestinal (GI) side effects of certain chemotherapeutic and pain medications. The most dangerous and well-understood example of this commensal bacteria-induced drug toxicity is the chemotherapeutic agent irinotecan (also called CPT-11), which produces frequent, intense, and dose-limiting diarrhea. The toxic effects of CPT-11 occur in the lower GI as a result of the sugar-metabolizing activity of a microbial enzyme, the bacterial ?-glucuronidase, which converts an inactive metabolite of CPT-11 into a "reactivated" cytotoxic form that damages the large intestine. The same mechanism of bacterial-mediated toxicity is responsible for ulcerations of the small intestine associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). This project aims to develop a new class of therapeutic adjuvants that selectively targets this deleterious activity of bacterial ?-glucuronidases to prevent or treat CPT-11-induced diarrhea without harming the commensal and symbiotic intestinal flora. We previously reported that oral delivery of a small molecule inhibitor (Inh-1) of this enzyme relieved the GI damage and bloody diarrhea caused by CPT-11 in mice. Inh-1 was not lethal to microbial or mammalian cells and did not block the activity of mammalian ?-glucuronidase. To further advance this technology, we propose to synthesize and characterize novel analogues of Inh-1 for potency, selectivity, and cytotoxicity in standard bacterial and mammalian protein and cellular assays.
We aim to engineer new molecules to possess little or no oral bioavailability to maximize the local therapeutic effects in the gut and minimize the potential for any systemic side effects. This phase of the project aims to identify a pharmaceutically superior molecule to Inh-1 that could serve as a lead series for further optimization in the next phase of this project, ultimately with the goal of identifying a proprietary drug for future clinical testing. The use of this technology s expected to extend to other chemotherapeutics and most NSAIDs that share this same mechanism of toxicity.
The serious side effects of some drugs can be prevented with a new class of medicines that target an unwanted activity of beneficial intestinal microbes without harming these microbes. We propose to synthesize and identify promising new drug candidates to prevent severe diarrhea associated with the widely used, but frequently toxic, chemotherapeutic agent irinotecan. This approach is not only expected to enhance the quality of life of cancer patients undergoing chemotherapy, but may also improve chemotherapeutic outcomes. Our technology may also be useful for other drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) that produce intestinal side effects with the same bacterial-based mechanism of toxicity.