In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation
ABSTRACT Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the Odilorhabdins, a novel antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a novel 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 E. coli EN122 (ESBL) or E. coli ATCC BAA-2469 (NDM-1), achieving an ED50 of 3.5 mg/kg 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 UTI model of E. coli UTI89, urine, bladder and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injecting 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or HRPT cells, 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 novel 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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Preprint| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
bioRxiv.org - (2020) vom: 18. Jan. Zur Gesamtaufnahme - year:2020 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Racine, Emilie [VerfasserIn] |
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| Links: |
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| doi: |
10.1101/329946 |
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| PPN (Katalog-ID): |
XBI000285838 |
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| 520 | |a ABSTRACT Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the Odilorhabdins, a novel antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a novel 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 E. coli EN122 (ESBL) or E. coli ATCC BAA-2469 (NDM-1), achieving an ED50 of 3.5 mg/kg 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 UTI model of E. coli UTI89, urine, bladder and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injecting 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or HRPT cells, 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 novel 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. | ||
| 700 | 1 | |a Nordmann, Patrice |e verfasserin |4 aut | |
| 700 | 1 | |a Pantel, Lucile |e verfasserin |4 aut | |
| 700 | 1 | |a Sarciaux, Matthieu |e verfasserin |4 aut | |
| 700 | 1 | |a Serri, Marine |e verfasserin |4 aut | |
| 700 | 1 | |a Houard, Jessica |e verfasserin |4 aut | |
| 700 | 1 | |a Villain-Guillot, Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Demord, Anthony |e verfasserin |4 aut | |
| 700 | 1 | |a Lundberg, Carina Vingsbo |e verfasserin |4 aut | |
| 700 | 1 | |a Gualtieri, Maxime |e verfasserin |4 aut | |
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