Premium
Novel Acyl Phosphate Mimics that Target PlsY, an Essential Acyltransferase in Gram‐Positive Bacteria
Author(s) -
Grimes Kimberly D.,
Lu YingJie,
Zhang YongMei,
Luna Vicki A.,
Hurdle Julian G.,
Carson Elizabeth I.,
Qi Jianjun,
Kudrimoti Sucheta,
Rock Charles O.,
Lee Richard E.
Publication year - 2008
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800218
Subject(s) - acyltransferase , acyltransferases , chemistry , acylation , biochemistry , acyl group , amide , bacteria , stereochemistry , substrate (aquarium) , antimicrobial , bacillus anthracis , enzyme , biosynthesis , organic chemistry , biology , genetics , ecology , alkyl , catalysis
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.