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Antimicrob Agents Chemother. 2018 Aug 27;62(9). pii: e01016-18. doi: 10.1128/AAC.01016-18. Print 2018 Sep.

In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation.

Author information

1
Nosopharm, Nîmes, France.
2
Emerging Antibiotic Resistance Unit, National Reference Center for Emerging Antibiotic Resistance, INSERM European Unit (LEA Paris, IAME, France), University of Fribourg, Fribourg, Switzerland.
3
Statens Serum Institut, Copenhagen, Denmark.
4
Nosopharm, Nîmes, France m.gualtieri@nosopharm.com.

Abstract

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.

KEYWORDS:

bacterial translation; carbapenem-resistant Enterobacteriaceae; inhibitor; preclinical candidate

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