Total Synthesis and Structure–Activity Relationships Study of Odilorhabdins, a New Class of Peptides Showing Potent Antibacterial Activity

Abstract

The spread of antibiotic-resistant pathogens is a growing concern, and new families of antibacterials are desperately needed. Odilorhabdins are a new class of antibacterial compounds that bind to the bacterial ribosome and kill bacteria through inhibition of the translation. NOSO-95C, one of the first member of this family, was synthesized for the first time, and then a structure-activity relationships study was performed to understand which groups are important for antibacterial activity and for inhibition of the bacterial translation. Based on this study an analogue showing improved properties compared to the parent compound was identified and showed promising in vitro and in vivo efficacy against Enterobacteriaceae.

Phenol‐Soluble‐Modulin‐Inspired Amphipathic Peptides Have Bactericidal Activity against Multidrug‐Resistant Bacteria

“…Among them, carbapenem‐resistant Enterobacteriaceae (CRE) has aroused great concern due to its rapid dissemination and high mortality rates . Carbapenemases, such as New Delhi metallo‐β‐lactamase‐1 (NDM‐1), produced by these strains are considered to result in the neutralization and thus ineffectiveness of β‐lactam antibiotics through hydrolysis . Moreover, cross‐resistance is becoming increasingly serious.…”

“…[2] Carbapenemases, such as New Delhi metallo-b-lactamase-1 (NDM-1), produced by these strains are considered to result in the neutralization and thus ineffectiveness of b-lactam antibiotics through hydrolysis. [3] Moreover,c ross-resistance is becoming increasingly serious. Bacteria have evolvedv arious ways to defend against frequently used antibiotics, such as daptomycin and vancomycin.…”

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

“…Two of the non-standard amino acids, Dab(βOH) and Dha, were not commercially available and were required for the total synthesis of NOSO-95C. We developed their synthesis on a multi-gram scale and reported the first total synthesis of NOSO-95C (Sarciaux et al, 2018). The 1 H NMR and LC-MS spectra and antibacterial activity of the natural and synthetic peptides were similar.…”

“…Based on these encouraging results and with a validated synthetic method, we initiated a medicinal chemistry program on NOSO-95C 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). Before starting this study, the inhibition of bacterial translation was identified as the principal mode of action of ODLs.…”

“…The combination of best modifications and of the shorter active sequence led to NOSO-95179 identified as a lead compound showing promising in vitro and in vivo antibacterial activity against Enterobacteriaceae (including CRE) and low toxicity (Pantel et al, 2018;Sarciaux et al, 2018). This compound was used as the starting point for a lead-optimization campaign.…”