title: Novel acyl phosphate mimics that target PlsY, an essential acyltransferase in gram-positive bacteria.
abstract: 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 alpha,alpha-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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 847 Monroe Ave, Memphis, TN 38163, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Grimes
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Luna
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Carson
authors.forename: Jianjun
authors.initials: J
authors.lastname: Qi
authors.forename: Sucheta
authors.initials: S
authors.lastname: Kudrimoti
authors.forename: Charles O
authors.initials: CO
authors.lastname: Rock
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D010710:Phosphates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D010710:Phosphates; C088150:plsX protein, bacteria; D000217:Acyltransferases