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In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation

Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on riboso...

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Autores principales: Racine, Emilie, Nordmann, Patrice, Pantel, Lucile, Sarciaux, Matthieu, Serri, Marine, Houard, Jessica, Villain-Guillot, Philippe, Demords, Anthony, Vingsbo Lundberg, Carina, Gualtieri, Maxime
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125496/
https://www.ncbi.nlm.nih.gov/pubmed/29987155
http://dx.doi.org/10.1128/AAC.01016-18
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author Racine, Emilie
Nordmann, Patrice
Pantel, Lucile
Sarciaux, Matthieu
Serri, Marine
Houard, Jessica
Villain-Guillot, Philippe
Demords, Anthony
Vingsbo Lundberg, Carina
Gualtieri, Maxime
author_facet Racine, Emilie
Nordmann, Patrice
Pantel, Lucile
Sarciaux, Matthieu
Serri, Marine
Houard, Jessica
Villain-Guillot, Philippe
Demords, Anthony
Vingsbo Lundberg, Carina
Gualtieri, Maxime
author_sort Racine, Emilie
collection PubMed
description Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against Escherichia coli EN122 (extended-spectrum β-lactamase [ESBL]) or E. coli ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED(50)) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with E. coli UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log(10) CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile.
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spelling pubmed-61254962018-09-17 In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation Racine, Emilie Nordmann, Patrice Pantel, Lucile Sarciaux, Matthieu Serri, Marine Houard, Jessica Villain-Guillot, Philippe Demords, Anthony Vingsbo Lundberg, Carina Gualtieri, Maxime Antimicrob Agents Chemother Experimental Therapeutics Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 μg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-β-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against Escherichia coli EN122 (extended-spectrum β-lactamase [ESBL]) or E. coli ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED(50)) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with E. coli UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log(10) CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 μM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile. American Society for Microbiology 2018-08-27 /pmc/articles/PMC6125496/ /pubmed/29987155 http://dx.doi.org/10.1128/AAC.01016-18 Text en Copyright © 2018 Racine et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Experimental Therapeutics
Racine, Emilie
Nordmann, Patrice
Pantel, Lucile
Sarciaux, Matthieu
Serri, Marine
Houard, Jessica
Villain-Guillot, Philippe
Demords, Anthony
Vingsbo Lundberg, Carina
Gualtieri, Maxime
In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
title In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
title_full In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
title_fullStr In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
title_full_unstemmed In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
title_short In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation
title_sort in vitro and in vivo characterization of noso-502, a novel inhibitor of bacterial translation
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125496/
https://www.ncbi.nlm.nih.gov/pubmed/29987155
http://dx.doi.org/10.1128/AAC.01016-18
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