Novel Acyl Phosphate Mimics that Target PlsY, an Essential Acyltransferase in Gram-Positive Bacteria

PlsY is a recently discovered acyltransferase that executes an essential step in membrane phospholipid biosynthesis in Gram‐ positive bacteria. By using a bioisosteric replacement approach to generate substrate‐based inhibitors of PlsY as potential novel antibacterial agents, a series of stabilized acyl phosphate mimetics, including acyl phosphonates, acyl α,α‐difluoromethyl phosphonates, acyl phosphoramides, reverse amide phosphonates, acyl sulfamates, and acyl sulfamides were designed and synthesized. Several acyl phosphonates, phosphoramides, and sulfamates were identified as inhibitors of PlsY from Streptococcus pneumoniae and Bacillus anthracis. As anticipated, these inhibitors were competitive inhibitors with respect to the acyl phosphate substrate. Antimicrobial testing showed the inhibitors to have generally weak activity against Gram‐positive bacteria with the exception of some acyl phosphonates, reverse amide phosphonates, and acyl sulfamates, which had potent activity against multiple strains of B. anthracis. Targeting phospholipid biosynthesis: Novel inhibitors of the PlsX/PlsY pathway to phosphatidic acid, a key intermediate in the biosynthesis of phospholipids in Gram‐positive bacteria have been discovered. Substrate mimics that incorporate various bioisosteric replacement head groups and acyl chains were revealed that demonstrate good enzyme inhibition, good antimicrobial activity, and low cytotoxicity.