Novel Acylphosphate 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. Using a bioisosteric replacement approach to generate substrate-based inhibitors of PlsY as potential novel antibacterial agents, a series of stabilized acylphosphate mimetics, including acylphosphonates, acyl αα,-difluoromethyl phosphonates, acyl phosphoramides, reverse amide phosphonates, acylsulfamates and acylsulfamides 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 acylphosphate substrate. Antimicrobial testing showed the inhibitors to have generally weak anti Gram-positive activity with the exception of some acyl phosphonates, reverse amide phosphonates, and acylsulfamates that had potent activity against multiple strains of Bacillus anthracis.