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Lantibiotics continue to offer an untapped pipeline for the development of novel antibiotics. We report here the discovery of a novel lantibiotic for the treatment of C. difficile infection (CDI). The leads were selected from a library of over 300 multiple substitution variants of the lantibiotic Mutacin 1140 (MU1140). Top performers were selected based on testing for superior potency, solubility, manufacturability, and physicochemical and/or metabolic stability in biologically-relevant systems. The best performers in vitro were further evaluated orally in the Golden Syrian hamster model of CDAD. In vivo testing ultimately identified OG716 as the lead compound, which conferred 100% survival and no relapse at 3 weeks post infection. MU1140-derived variants are particularly attractive for further clinical development considering their novel mechanism of action., Competing Interests: JX, MEP and WJW had a financial interest in this study as Oragenics sponsored work performed in their respective laboratories. JAK was an Intrexon employees during the data collection and initial data analysis. AWD was an Oragenics stockholder and employee during data collection and initial data analysis. JHP and MH had a financial interest in Oragenics as stockholders and employees during data collection, analysis and writing of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.