ORALLY ACTIVE METABOLITE THERAPY AGAINST C. DIFFICILE INFECTION

Project SummaryC. difficile infection is an extremely debilitating disease with high mortality rates and expensive medical carecosts. Current antibiotic therapies such as vancomycin and metronidazole leave patients prone to relapse;therefore, more effective therapeutic approaches are actively sought after. A recently published report from ourlaboratory demonstrated that a cathelicidin mimic compound CSA13 could inhibit C. difficile primary infectionand vancomycin-associated relapse in mice. We found that the oral administration of CSA13 modulated theintestinal microbiome in C. difficile-infected mice. Metabolomic analysis revealed a specific pattern of fecalmetabolites associated with the therapeutic effect of CSA13. Oral administration of four metabolites mimickedthe protective effect of CSA13. Metabolite treatment, like CSA13 treatment, prevented vancomycin-associatedrelapse of C. difficile-infected mice. Metabolites may be a potential therapeutic agent against primary C. difficileinfection and preventing C. difficile relapse. However, it is necessary to optimize the regimen for maximalefficacy and characterize its impact on C. difficile pathophysiology, intestinal microbiome, and host immuneresponses. This application proposes to determine (1) whether the metabolites inhibit C. difficile toxinproduction and spore generation; (2) whether metabolites exert a cytoprotective effect in epithelial cells andsuppress toxin-mediated immune responses. We will optimize the dosing regimen of mixed metabolites formaximal protection against CDI. The overall impact of this study will discover a novel way of treating CDI.Specific protective metabolite therapy is safer, more convenient, and more straightforward than fecalmicrobiota transplantation.