@article{82909d8b573c4fa285cbfb504c2cf9d9,
title = "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 (1,918 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.",
keywords = "Antibiotic, Antibiotic resistance, Antimicrobial peptide, Bacteriocin, Bioavailability, Lanthipeptide, Lantibiotic, Mutacin, Mutagenesis, Nisin",
author = "Pulse, {Mark E.} and Weiss, {William J.} and Kers, {Johan A.} and DeFusco, {Anthony W.} and Park, {Jae H.} and Martin Handfield",
note = "Funding Information: Current and past employees of Oragenics and Intrexon are acknowledged for their contribution to the work described in this report. In particular, R. Eryl Sharp is acknowledged for his work on the improvements to methods to build, purify, and characterize MU1140 and variants; and Sheela Muley, Melissa Mayo, and Jeffrey Colbeck helped with the development of analytical methods to extract, purify, and characterize MU1140 and variants, designed DNA vectors and genetic constructions, and produced and characterized MU1140 variants. We also thank Albert G. Fosmoe, II, Bruce Tilley, Gabriela Philips, Mathoor (Siv) Sivaram, Joel Ngoje, Fernando Anazco, Zaxton Lamon, Emily Richeson, and Vicky DaSilva, who contributed to the production, purification, and testing/characterization of MU1140 and variants. M.H. is grateful to Charles River Laboratories (Nataliya Sadekova, Michelle King, Kevin Norton, and Andreanne Mor-ency), AIT Biosciences (Brad King), and Synergy Partners (Shelley Ching and Jim MacDonald) for their help in the design and execution of several of the animal studies and analytical assays reported in this work. J.H.P. is grateful to the NMR facility at the University of Florida (Ion Ghiviriga) and Peptide International (Patricia Y. Coxon) for extended NMR study and elemental analysis, respectively. M.H. and J.H.P. thank Alan Joslyn for critical review of the manuscript. Publisher Copyright: Copyright {\textcopyright} 2019 American Society for Microbiology. All Rights Reserved.",
year = "2019",
month = apr,
doi = "10.1128/AAC.01904-18",
language = "English",
volume = "63",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "4",
}