Racine, Emilie Nordmann, Patrice Pantel, Lucile Sarciaux, Matthieu Serri, Marine Houard, Jessica Villain-Guillot, Philippe Demords, Anthony Lundberg, Carina Vingsbo Gualtieri, Maxime 2018-09-01 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. application/pdf https://folia.unifr.ch/global/documents/307465 https://folia.unifr.ch/documents/307465/files/nor_vvc.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.01016-18 info:eu-repo/semantics/openAccess License undefined Antimicrobial Agents and Chemotherapy. - 2018, vol. 62, no. 9, p. e01016-18 info:eu-repo/classification/udc/57 In vitro and in vivo characterization of noso-502, a novel inhibitor of bacterial translation http://purl.org/coar/resource_type/c_6501