Pseudolipasin A is a specific inhibitor for phospholipase A2 activity of Pseudomonas aeruginosa cytotoxin ExoU.
A number of bacterial pathogens utilize the type III secretion pathway to deliver effector proteins directly into the host cell cytoplasm. Certain strains of Pseudomonas aeruginosa associated with acute infections express a potent cytotoxin, exoenzyme U (ExoU), that is delivered via the type III secretion pathway directly into contacting host cells. Once inside the mammalian cell, ExoU rapidly lyses the intoxicated cells via its phospholipase A(2) (PLA(2)) activity. A high-throughput cell-based assay was developed to screen libraries of compounds for those capable of protecting cells against the cytotoxic effects of ExoU. A number of compounds were identified in this screen, including one group that blocks the intracellular activity of ExoU. In addition, these compounds specifically inhibited the PLA(2) activity of ExoU in vitro, whereas eukaryotic secreted PLA(2) and cytosolic PLA(2) were not inhibited. This novel inhibitor of ExoU-specific PLA(2) activity, named pseudolipasin A, may provide a new lead for virulence factor-based therapeutic design.
Lee
Vincent T
VT
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA. vtlee@umd.edu
Pukatzki
Stefan
S
Sato
Hiromi
H
Kikawada
Eriya
E
Kazimirova
Anastasia A
AA
Huang
Jin
J
Li
Xiaohua
X
Arm
Jonathan P
JP
Frank
Dara W
DW
Lory
Stephen
S
D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003603:Cytotoxins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005449:Fluorenes / Q000737:chemistry / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
D001426:Bacterial Proteins; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D005449:Fluorenes; D037521:Virulence Factors; C518675:pseudolipasin A; C111749:pseudomonas exoprotein A protein, Pseudomonas aeruginosa; D010741:Phospholipases A; D054467:Phospholipases A2