10.1371/journal.pone.0197467
Johan A. Kers
Johan A.
Kers
Anthony W. DeFusco
Anthony W.
DeFusco
Jae H. Park
Jae H.
Park
Jin Xu
Jin
Xu
Mark E. Pulse
Mark E.
Pulse
William J. Weiss
William J.
Weiss
Martin Handfield
Martin
Handfield
OG716: Designing a fit-for-purpose lantibiotic for the treatment of <i>Clostridium difficile</i> infections
Public Library of Science
2018
substitution variants
performer
OG 716
lantibiotic Mutacin 1140
fit-for-purpose lantibiotic
vivo testing
novel antibiotics
novel lantibiotic
infections Lantibiotics
MU 1140-derived variants
novel mechanism
CDI
hamster model
CDAD
3 weeks post infection
biologically-relevant systems
2018-06-12 18:01:08
Dataset
https://plos.figshare.com/articles/dataset/OG716_Designing_a_fit-for-purpose_lantibiotic_for_the_treatment_of_i_Clostridium_difficile_i_infections/6494786
<div><p>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 <i>C</i>. <i>difficile</i> 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 <i>in vitro</i> were further evaluated orally in the Golden Syrian hamster model of CDAD. <i>In vivo</i> 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.</p></div>