[Show abstract][Hide abstract] ABSTRACT: 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.