Abstract
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.
Highlights
C. difficile continues to be an urgent threat in the hospital setting according to the Centers for Disease Control and Prevention (CDC), and one of the most common healthcare-associated infections worldwide, causing up to 250,000 infections per year, 14,000 deaths and resulting in at least 1 billion dollars in excess medical costs per year in the United States alone [1]
The test compounds were engineered by pyramiding multiple amino acid substitutions in lanA, the primary structural gene encoding the pro-peptide that matures to form Mutacin 1140 (MU1140) based on performance improvements observed from single amino acid substitutions during previous studies [22, 28]
The top 8 performers from the in vitro assay screening process were produced at the 100 mg scale and tested against OG253 (MU1140-F1I) and vancomycin to evaluate their in vivo efficacy
Summary
C. difficile continues to be an urgent threat in the hospital setting according to the Centers for Disease Control and Prevention (CDC), and one of the most common healthcare-associated infections worldwide, causing up to 250,000 infections per year, 14,000 deaths and resulting in at least 1 billion dollars in excess medical costs per year in the United States alone [1]. Deaths related to CDI increased 400% between 2000 and 2007, in part because of the emergence of a more virulent strain. Resistance to the antibiotics used to initially treat CDI (metronidazole and vancomycin) is not yet a significant problem, but may contribute to the development of resistance to vancomycin in other bacterial species. CDI mostly occur in people who have had both recent medical care and who were treated with antibiotics, and more frequently in hospitalized or recently hospitalized patients [2].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
