期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 28, 期 11, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2020.115469
关键词
Odilorhabdins; Novel antibiotic class; SAR; Inhibition of bacterial translation; Novel amino acids
资金
- [European Gram-negative Antibacterial Engine (ENABLE) project WP5b] from the Innovative Medicines Initiative (IMI) Joint Undertaking from the European Union's Seventh Framework Program (FP7/20072013) [115583]
- European Federation of Pharmaceutical Industry Associations (EFPIA) companies
- OSEO [A1010014J]
- Region Languedoc-Roussillon [A1010014J]
- DGA [122906117]
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 (Delta tolC) to evaluate the impact of efflux on the antibacterial activity.
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