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Antimicrob Agents Chemother. 2019 Jan 22. pii: AAC.01904-18. doi: 10.1128/AAC.01904-18. [Epub ahead of print]

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

Author information

1
PreClinical Services, UNT System College of Pharmacy, 3500 Camp Bowie Blvd., Fort Worth, TX 76107. USA.
2
Intrexon Corp., Industrial Products Division, South San Francisco, CA 94080. USA.
3
Oragenics, Inc. 13700 Progress Blvd, Alachua, FL 32608. USA.
4
Oragenics, Inc. 13700 Progress Blvd, Alachua, FL 32608. USA mhandfield@oragenics.com.

Abstract

Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of C. 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 challenged orally in the Golden Syrian hamster model of Clostridium difficile associated disease CDAD in a dose-response format, resulting in selection of OG716 as the lead compound. This lantibiotic was characterized by an ED50 of 23.85 mg/Kg/day (10.97 μmole/Kg/day) in this model. Upon oral administration of the maximum feasible dose (≥1,918 mg/Kg/day), no observable toxicities and side effects were noted and no effect on intestinal motility was observed. Compartmentalization to the GI tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics in 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.

PMID:
30670434
DOI:
10.1128/AAC.01904-18

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