9BIC

N-Me-D-Leu2,D-Thr5-clovibactin

Summary for 9BIC

• Entry DOI: 10.2210/pdb9bic/pdb
• Descriptor: PHE-MLU-DLY-SER-DTH-ALA-LEU-LEU, CADMIUM ION, SULFATE ION, ... (4 entities in total)
• Functional Keywords: depsipeptide, antibiotic
• Biological source: Eleftheria
• Total number of polymer chains: 8
• Total formula weight: 7986.80

Authors

Kreutzer, A.G.,Griffin, J.G.,Nowick, J.S. (deposition date: 2024-04-23, release date: 2024-09-18)

Primary citation

Brunicardi, J.E.H.,Griffin, J.H.,Ferracane, M.J.,Kreutzer, A.G.,Small, J.,Mendoza, A.T.,Ziller, J.W.,Nowick, J.S.
Structure-Activity Relationship Studies of the Peptide Antibiotic Clovibactin.
J.Org.Chem., 89:12479-12484, 2024

PubMed Abstract: 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-(2,3)-3-hydroxyasparagine-OH that enables structure-activity relationship studies of clovibactin. An alanine scan reveals that residues Phe, d-Leu, Ser, Leu, and Leu are important for antibiotic activity. The side-chain amide group of the rare d-Hyn 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 -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.

PubMed: 39178334
DOI: 10.1021/acs.joc.4c01414

Experimental method

X-RAY DIFFRACTION (2.05 Å)