@article {Racine329946, author = {Emilie Racine and Patrice Nordmann and Lucile Pantel and Matthieu Sarciaux and Marine Serri and Jessica Houard and Philippe Villain-Guillot and Anthony Demord and Carina Vingsbo Lundberg and Maxime Gualtieri}, title = {In vitro and In vivo characterization of NOSO-502, a novel inhibitor of bacterial translation}, elocation-id = {329946}, year = {2018}, doi = {10.1101/329946}, publisher = {Cold Spring Harbor Laboratory}, 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.}, URL = {https://www.biorxiv.org/content/early/2018/05/24/329946}, eprint = {https://www.biorxiv.org/content/early/2018/05/24/329946.full.pdf}, journal = {bioRxiv} }