Pharmacological, Toxicological, and Dose Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile -Associated Infection

Abstract

Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of Clostridium difficile infection. The lead compounds were selected from a library of over 700 single-and multiple-substitution variants of the lantibiotic mutacin 1140 (MU1140). The best performers in vitro and in vivo were further used to challenge Golden Syrian hamsters orally in a Golden Syrian hamster model of Clostridium difficile-associated disease (CDAD) in a dose-response format, resulting in the selection of OG716 as the lead compound. This lantibiotic was characterized by a 50% effective dose of 23.85 mg/kg of body weight/day (10.97 mol/kg/day) in this model. Upon oral administration of the maximum feasible dose (Ն1,918 mg/kg/day), no observable toxicities or side effects were noted, and no effect on intestinal motility was observed. Compartmentalization to the gastrointestinal tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics for the treatment of several indications and are particularly attractive considering their novel mechanism of action. Based on the currently available data, OG716 has an acceptable profile for further development for the treatment of CDAD.

Bacteriocins as a new generation of antimicrobials: toxicity aspects and regulations

“…Additionally, OG716, a derivative of mutacin 1140, which is considered as a potential candidate for CDAD treatment, has shown no toxicity or side effects upon oral administration in Golden Syrian Hamster; hence, it may progress toward clinical development (Pulse et al . 2019 ).…”

In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile

“…The effectiveness of OPS-2071 and other drugs was assessed in a hamster model of CDI. This model is the current gold standard used to assess potential efficacy in the treatment of CDI (26)(27)(28)(29). The survival curve for each drug tested in this study is shown in Fig.…”

“…With respect to the efficacy in animal models, many therapeutic agents have been tested in the hamster model of clindamycin-induced CDI (26)(27)(28)(29). Specifically, we organized our animal model with reference to an animal model in which clindamycin is administrated one day after the C. difficile infection (27), because CDI is normally induced by administration of antibiotics with on February 1, 2021 by guest http://aac.asm.org/ Downloaded from pre-existing C. difficile in the intestine. In addition, the MIC of C. difficile ATCC 43255 to clindamycin is reported as 8µg/mL (35).…”

Bacteriocins: An Overview of Antimicrobial, Toxicity, and Biosafety Assessment by in vivo Models

“…Second, the route of administration determines the onset and the duration of the pharmacological effect, the efficacy, and the adverse effects of drugs. The main routes of bacteriocin administration, such as intranasal ( McCaughey et al, 2016a , b ), intragastric ( Wongsen et al, 2019 ), intraperitoneal ( Piper et al, 2012 ; Sahoo et al, 2017 ), subcutaneous ( Kers et al, 2018a , b ; Pulse et al, 2019 ), and topical ( Van Staden et al, 2016 ; Cebrián et al, 2019 ) have demonstrated excellent efficacy in murine models. However, the efficacy of the different routes of administration has not been directly compared and likely depends on the pathogen targeted ( Lohans and Vederas, 2012 ).…”