Synthesis of new peptide inhibitors of the meso-diaminopimelate-adding enzyme

Article abstract of DOI:10.1016/0223-5234(92)90021-R

In order to obtain inhibitors of the meso-diaminopimelate-adding enzyme, which catalyzes an early reaction in the biosynthesis of bacterial peptidoglycan, several new peptide derivatives of general formula, N(α)-propionyl-L-alanyl-D (or ambo)-Xaa were synthesized: four transition-state analogs (Xaa = phosphinothricin, homocysteic acid, buthionine sulfoximine, buthionine sulfoximine phosphate), three analogs of γ-D-glytamyl phosphate (Xaa = 3-phosphonoacetamideo-alanine, 3-phosphonomethylamino-aspartic acid, 2-amino-6-phosphonohexanoic acid), and one derivative with Xaa = ornithine. After preincubation with partially purified meso-diaminopimelate-adding enzyme from Escherichia coli, peptide derivatives with Xaa - buthionine sulfoximine, 3-phosphonoacetamido-alanine and 2-amino-6-phosphonohexanoic acid appeard to be among the best inhibitors obtained up to date, with I₅₀ values between 0.6 and 1.2 mM. When the two first compounds were tested for in vitro antibacterial activity, they gave negative results.