In vitro and in vivo characterization of noso-502, a novel inhibitor of bacterial translation
- Racine, Emilie Nosopharm, Nîmes, France
- Nordmann, Patrice Emerging Antibiotic Resistance Unit, National Reference Center for Emerging Antibiotic Resistance, INSERM European Unit (LEA Paris, IAME, France), University of Fribourg, Switzerland
- Pantel, Lucile Nosopharm, Nîmes, France
- Sarciaux, Matthieu Nosopharm, Nîmes, France
- Serri, Marine Nosopharm, Nîmes, France
- Houard, Jessica Nosopharm, Nîmes, France
- Villain-Guillot, Philippe Nosopharm, Nîmes, France
- Demords, Anthony Emerging Antibiotic Resistance Unit, National Reference Center for Emerging Antibiotic Resistance, INSERM European Unit (LEA Paris, IAME, France), University of Fribourg, Switzerland
- Lundberg, Carina Vingsbo Statens Serum Institut, Copenhagen, Denmark
- Gualtieri, Maxime Nosopharm, Nîmes, France
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01.09.2018
Published in:
- Antimicrobial Agents and Chemotherapy. - 2018, vol. 62, no. 9, p. e01016-18
English
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 (ED50) 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 log10 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.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 323464
- DOI 10.1128/AAC.01016-18
- Persistent URL
- https://folia.unifr.ch/unifr/documents/307465
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