OG716: Designing a fit-for-purpose lantibiotic for the treatment of <i>Clostridium difficile</i> infections
Johan A. Kers
Anthony W. DeFusco
Jae H. Park
Jin Xu
Mark E. Pulse
William J. Weiss
Martin Handfield
10.1371/journal.pone.0197467
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>
2018-06-12 18:01:08
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