PHOSPHINATE INHIBITORS OF THE D-GLUTAMIC ACID-ADDING ENZYME OF PEPTIDOGLYCAN BIOSYNTHESIS

We report the synthesis and initial evaluation of the first effective inhibitors of the D-glutamic acid-adding enzyme (UDP-N-acetylmuramoyl- L-alanine:D-glutamate ligase or MurD). This enzyme plays a key role in bacterial peptidoglycan biosynthesis and is therefore a target for an tibiotic design. Phosphinic acid 3 is a dipeptide analog linked to uri dine diphosphate by a hydrophobic spacer. It is a good inhibitor of th e enzyme (IC50 = 0.68 mu M) as it closely resembles the tetrahedral in termediate that is presumed to form in the ligation reaction. Compound 4 lacks the terminal UMP group, and compound 5 lacks both the linker and UDP functionalities. These are less effective inhibitors of the en zyme with IC50 values of 29 mu M and > 1 mM, respectively. Preincubati on of the enzyme in the presence of inhibitor 3 and ATP does not resul t in irreversible inhibition or in the formation of a slowly decomplex ing species, suggesting that the phosphinic acid is not phosphorylated in the active site.