Structure-activity relationship studies on the inhibition of the bacterial translation of novel Odilorhabdins analogues. Issue 11 (1st June 2020)

• Record Type: Journal Article
• Authors: Loza, Einars; Sarciaux, Matthieu; Ikaunieks, Martins; Katkevics, Martins; Kukosha, Tatyana; Trufilkina, Nadezhda; Ryabova, Victoria; Shubin, Kirill; Pantel, Lucile; Serri, Marine; Huseby, Douglas L; Cao, Sha; Yadav, Kavita; Hjort, Karin; Hughes, Diarmaid; Gualtieri, Maxime; Suna, Edgars; Racine, Emilie
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 11(2020)
• Publication Date: 2020-06-01
• Subjects: Odilorhabdins -- Novel antibiotic class -- SAR -- Inhibition of bacterial translation -- Novel amino acids; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115469
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: 2 positions of a lead compound from a novel antibiotic class have been modified. Objective: improve the inhibition of the bacterial translation of the lead compound. 13 previously unreported non-proteinogenic amino acids have been synthesized. 20 analogues have been obtained and inhibition of the bacterial translation evaluated. Important structure–activity relationships of this new class have been found. Abstract: 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 (Δ tolC ) to evaluate the impact of efflux on the antibacterial activity.