Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues.

A structure-activity relationship (SAR) study of NOSO-95179, a nonapeptide from the Odilorhabdin class of antibacterials, was performed by systematic variations of amino acids in positions 2 and 5 of the peptide. A series of non-proteinogenic amino acids was synthesized in high enantiomeric purity from Williams' chiral diphenyloxazinone by highly diastereoselective alkylation or by aldol-type reaction. NOSO-95179 analogues for SAR studies were prepared using solid-phase peptide synthesis. Inhibition of bacterial translation by each of the synthesized Odilorhabdin analogues was measured using an in vitro test. For the most efficient analogues, antibacterial efficacy was measured against two wild-type Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae) and against an efflux defective E. coli strain (ΔtolC) to evaluate the impact of efflux on the antibacterial activity.

From Worms to Drug Candidate: The Story of Odilorhabdins, a New Class of Antimicrobial Agents.

A major issue currently facing medicine is antibiotic resistance. No new class of antibiotics for the treatment of Gram-negative infections has been introduced in more than 40 years. We screened a collection of Xenorhabdus and Photorhabdus strains in the quest to discover new structures that are active against the most problematic multidrug-resistant bacteria. These species are symbiotic bacteria of entomopathogenic nematodes and their life cycle, the richness of the bacteria's genome in non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) genes, and their propensity to produce secondary metabolites with a large diversity of chemical structures make them a good starting point to begin an ambitious drug discovery program. Odilorhabdins (ODLs), a novel antibacterial class, were identified from this campaign. These compounds inhibit bacterial translation by binding to the small ribosomal subunit at a site not exploited by current antibiotics. Following the development of the total synthesis of this family of peptides, a medicinal chemistry program was started to optimize their pharmacological properties. NOSO-502, the first ODL preclinical candidate was selected. This compound is currently under preclinical development for the treatment of multidrug-resistant Gram-negative infections in hospitalized patients.