<i>In Vitro</i> and <i>In Vivo</i> Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation

Abstract

Antibacterial activity screening of a collection of <i>Xenorhabdus</i> 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 <i>Enterobacteriaceae</i> strains and carbapenem-resistant <i>Enterobacteriaceae</i> (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 <i>Escherichia coli</i> EN122 (extended-spectrum β-lactamase [ESBL]) or <i>E. coli</i> 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 <i>E. coli</i> 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 <i>Enterobacteriaceae</i>, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable <i>in vitro</i> safety profile.