OG716: Designing a fit-for-purpose lantibiotic for the treatment of Clostridium difficile infections

Johan A. Kers; Anthony W. DeFusco; Jae H. Park; Jin Xu; Mark E. Pulse; William J. Weiss; Martin Handfield

doi:10.1371/journal.pone.0197467

OG716: Designing a fit-for-purpose lantibiotic for the treatment of Clostridium difficile infections

Johan A. Kers, Anthony W. DeFusco, Jae H. Park, Jin Xu, Mark E. Pulse, William J. Weiss, Martin Handfield

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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.

Original language	English
Article number	e0197467
Journal	PLoS ONE
Volume	13
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0197467
State	Published - Jun 2018

Access to Document

10.1371/journal.pone.0197467

Cite this

@article{d620c4190239455b89851a54947d2c33,

title = "OG716: Designing a fit-for-purpose lantibiotic for the treatment of Clostridium difficile infections",

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.",

author = "Kers, {Johan A.} and DeFusco, {Anthony W.} and Park, {Jae H.} and Jin Xu and Pulse, {Mark E.} and Weiss, {William J.} and Martin Handfield",

note = "Publisher Copyright: {\textcopyright} 2018 Kers et al.",

year = "2018",

month = jun,

doi = "10.1371/journal.pone.0197467",

language = "English",

volume = "13",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "6",

}

TY - JOUR

T1 - OG716

T2 - Designing a fit-for-purpose lantibiotic for the treatment of Clostridium difficile infections

AU - Kers, Johan A.

AU - DeFusco, Anthony W.

AU - Park, Jae H.

AU - Xu, Jin

AU - Pulse, Mark E.

AU - Weiss, William J.

AU - Handfield, Martin

PY - 2018/6

Y1 - 2018/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048433563&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0197467

DO - 10.1371/journal.pone.0197467

M3 - Article

C2 - 29894469

AN - SCOPUS:85048433563

SN - 1932-6203

VL - 13

JO - PLoS ONE

JF - PLoS ONE

IS - 6

M1 - e0197467

ER -

OG716: Designing a fit-for-purpose lantibiotic for the treatment of Clostridium difficile infections

Abstract

Access to Document

Other files and links

Fingerprint

Cite this