In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation

Racine, E.; Nordmann, P.; Pantel, L.; Sarciaux, M.; Serri, M.; Houard, J.; Villain-Guillot, P.; Demord, A.; Vingsbo Lundberg, C.; Gualtieri, M.

doi:10.1101/329946

bioRxiv · 10.1101/329946

In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation

Racine, E.·Nordmann, P.·Pantel, L.·Sarciaux, M.·Serri, M.·Houard, J.·Villain-Guillot, P.·Demord, A.·Vingsbo Lundberg, C.·Gualtieri, M.

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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 g/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-{beta}-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 M. 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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Racine, E., Nordmann, P., Pantel, L., Sarciaux, M., Serri, M., Houard, J., Villain-Guillot, P., Demord, A., Vingsbo Lundberg, C., Gualtieri, M.. 2018-05-24. In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation. https://doi.org/10.1101/329946

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