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

Abstract 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 -glutamyl phosphate (Xaa = 3-phosphonoacetamido-alanine, 3-phosphonomethylaminoaspartic 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 appeared to be among the best inhibitors obtained up to date, with I 50 values between 0.6 and 1.2 mM. When the two first compounds were tested for in vitro antibacterial activity, they gave negative results.