Abstract
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.
Highlights
The efforts of the pharmaceutical industry to generate new highly potent antibiotics with novel mechanisms of action have weakened dramatically over the last three decades for economic, scientific, or strategic reasons, resulting in the decline of the discovery of new classes of antibacterials
We identified four large non-ribosomal peptide synthetase (NRPS)-coding genes in the genome of the producer X. nematophila as the putative biosynthetic gene cluster using anti-SMASH, a secondary metabolite gene cluster prediction software
We evaluated the antibacterial activity of analogs against Enterobacteriaceae (E. coli and K. pneumoniae) and their potential to inhibit bacterial translation to help drive preliminary structure-activity relationships (SAR) studies
Summary
The efforts of the pharmaceutical industry to generate new highly potent antibiotics with novel mechanisms of action have weakened dramatically over the last three decades for economic, scientific, or strategic reasons, resulting in the decline of the discovery of new classes of antibacterials. Based on these encouraging results and with a validated synthetic method, we initiated a medicinal chemistry program on NOSO95C to study the structure-activity relationships (SAR) of ODLs with the objective to better understand the role of each amino acid for the antibacterial activity and the inhibition of bacterial translation (Sarciaux et al, 2018). Replacing Dab(βOH)3 by alanine resulted in a four-fold gain in antibacterial activity and in the same level of inhibition of bacterial translation than that of NOSO-95C.
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