Newly discovered and characterized antivirulence compounds inhibit bacterial mono-ADP-ribosyltransferase toxins.
The mono-ADP-ribosyltransferase toxins are bacterial virulence factors that contribute to many disease states in plants, animals, and humans. These toxins function as enzymes that target various host proteins and covalently attach an ADP-ribose moiety that alters target protein function. We tested compounds from a virtual screen of commercially available compounds combined with a directed poly(ADP-ribose) polymerase (PARP) inhibitor library and found several compounds that bind tightly and inhibit toxins from Pseudomonas aeruginosa and Vibrio cholerae. The most efficacious compounds completely protected human lung epithelial cells against the cytotoxicity of these bacterial virulence factors. Moreover, we determined high-resolution crystal structures of the best inhibitors in complex with cholix toxin to reveal important criteria for inhibitor binding and mechanism of action. These results provide new insight into development of antivirulence compounds for treating many bacterial diseases.
Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Zachari
Z
Turgeon
René
R
Jørgensen
Danielle
D
Visschedyk
Patrick R
PR
Edwards
Sarah
S
Legree
Caroline
C
McGregor
Robert J
RJ
Fieldhouse
Dev
D
Mangroo
Matthieu
M
Schapira
A Rod
AR
Merrill
D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors*; D020727:ADP-Ribosylation Factors / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011550:Pseudomonas aeruginosa / Q000201:enzymology
D000900:Anti-Bacterial Agents; D001427:Bacterial Toxins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D036002:ADP Ribose Transferases; D020727:ADP-Ribosylation Factors; C529269:cholix toxin, Vibrio cholerae