9bic

Publication Abstract from PubMed

Our laboratory reported the chemical synthesis and stereochemical assignment of the recently discovered peptide antibiotic clovibactin. The current paper reports an improved, gram-scale synthesis of the amino acid building block Fmoc-(2R,3R)-3-hydroxyasparagine-OH that enables structure-activity relationship studies of clovibactin. An alanine scan reveals that residues Phe(1), d-Leu(2), Ser(4), Leu(7), and Leu(8) are important for antibiotic activity. The side-chain amide group of the rare d-Hyn(5) residue is not essential to activity and can be replaced with a methyl group with a moderate loss of activity. An acyclic clovibactin analogue reveals that the macrolactone ring is essential to antibiotic activity. The enantiomer of clovibactin is active, albeit somewhat less so than clovibactin. A conformationally constrained clovibactin analogue retains moderate antibiotic activity, while a backbone N-methylated analogue is almost completely inactive. X-ray crystallography of these two analogues reveals that the macrolactone ring adopts a crown-like conformation that binds anions.

Structure-Activity Relationship Studies of the Peptide Antibiotic Clovibactin.,Brunicardi JEH, Griffin JH, Ferracane MJ, Kreutzer AG, Small J, Mendoza AT, Ziller JW, Nowick JS J Org Chem. 2024 Sep 6;89(17):12479-12484. doi: 10.1021/acs.joc.4c01414. Epub , 2024 Aug 23. PMID:39178334^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.