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

Loza, E.; Sarciaux, M.; Ikaunieks, M.; Katkevics, M.; Kukosha, T.; Trufilkina, N.; Ryabova, V.; Shubin, K.; Pantel, L.; Serri, M.; Huseby, D. L.; Cao, S.; Yadav, K.; Hjort, K.; Hughes, D.; Gualtieri, M.; Suna, E.; Racine, E. Bioorg. Med. Chem. 2020, 28, 115469.

DOI: 10.1016/j.bmc.2020.115469

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 analogs for SAR studies were prepd. using solid-​phase peptide synthesis.  Inhibition of bacterial translation by each of the synthesized Odilorhabdin analogs was measured using an in vitro test.  For the most efficient analogs, 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.