Biomaterial Database

Newly discovered and characterized antivirulence compounds inhibit bacterial mono-ADP-ribosyltransferase toxins. 2011

Zachari Turgeon, and René Jørgensen, and Danielle Visschedyk, and Patrick R Edwards, and Sarah Legree, and Caroline McGregor, and Robert J Fieldhouse, and Dev Mangroo, and Matthieu Schapira, and A Rod Merrill

Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.

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.

UI	MeSH Term	Description	Entries
D011550	Pseudomonas aeruginosa	A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. aeruginosa is a major agent of nosocomial infection.	Bacillus aeruginosus,Bacillus pyocyaneus,Bacterium aeruginosum,Bacterium pyocyaneum,Micrococcus pyocyaneus,Pseudomonas polycolor,Pseudomonas pyocyanea
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D002470	Cell Survival	The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.	Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067856	Poly(ADP-ribose) Polymerase Inhibitors	Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES.	Inhibitors of Poly(ADP-ribose) Polymerase,PARP Inhibitor,Poly(ADP-Ribose) Polymerase Inhibitor,Poly(ADP-ribosylation) Inhibitor,Inhibitors of Poly(ADP-ribose) Polymerases,PARP Inhibitors,Poly(ADP-ribosylation) Inhibitors,Inhibitor, PARP,Inhibitors, PARP
D000900	Anti-Bacterial Agents	Substances that inhibit the growth or reproduction of BACTERIA.	Anti-Bacterial Agent,Anti-Bacterial Compound,Anti-Mycobacterial Agent,Antibacterial Agent,Antibiotics,Antimycobacterial Agent,Bacteriocidal Agent,Bacteriocide,Anti-Bacterial Compounds,Anti-Mycobacterial Agents,Antibacterial Agents,Antibiotic,Antimycobacterial Agents,Bacteriocidal Agents,Bacteriocides,Agent, Anti-Bacterial,Agent, Anti-Mycobacterial,Agent, Antibacterial,Agent, Antimycobacterial,Agent, Bacteriocidal,Agents, Anti-Bacterial,Agents, Anti-Mycobacterial,Agents, Antibacterial,Agents, Antimycobacterial,Agents, Bacteriocidal,Anti Bacterial Agent,Anti Bacterial Agents,Anti Bacterial Compound,Anti Bacterial Compounds,Anti Mycobacterial Agent,Anti Mycobacterial Agents,Compound, Anti-Bacterial,Compounds, Anti-Bacterial
D001427	Bacterial Toxins	Toxic substances formed in or elaborated by bacteria; they are usually proteins with high molecular weight and antigenicity; some are used as antibiotics and some to skin test for the presence of or susceptibility to certain diseases.	Bacterial Toxin,Toxins, Bacterial,Toxin, Bacterial
D020128	Inhibitory Concentration 50	The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.	IC50,Concentration 50, Inhibitory
D020727	ADP-Ribosylation Factors	MONOMERIC GTP-BINDING PROTEINS that were initially recognized as allosteric activators of the MONO(ADP-RIBOSE) TRANSFERASE of the CHOLERA TOXIN catalytic subunit. They are involved in vesicle trafficking and activation of PHOSPHOLIPASE D. This enzyme was formerly listed as EC 3.6.1.47	ADP-Ribosylation Factor,ARF Protein Cofactor,ADP Ribosylation Factor,ADP Ribosylation Factors
D036002	ADP Ribose Transferases	Enzymes that transfer the ADP-RIBOSE group of NAD or NADP to proteins or other small molecules. Transfer of ADP-ribose to water (i.e., hydrolysis) is catalyzed by the NADASES. The mono(ADP-ribose)transferases transfer a single ADP-ribose. POLY(ADP-RIBOSE) POLYMERASES transfer multiple units of ADP-ribose to protein targets, building POLY ADENOSINE DIPHOSPHATE RIBOSE in linear or branched chains.	ADP-Ribosyltransferase,Mono(ADP-Ribose) Transferases,NAD(P)(+)-Arginine ADP-Ribosyltransferase,NAD+ ADP-Ribosyltransferase,ADP Ribose Transferase,ADPRT,ADPRTs,ART Transferase,ART Transferases,ARTase,ARTases,Mono ADP-ribose Transferases,Mono ADPribose Transferase,Mono ADPribose Transferases,Mono(ADP-Ribose) Transferase,Mono(ADP-Ribosyl)transferase,Mono(ADPribosyl)transferase,Mono-ADP-Ribosyltransferase,MonoADPribosyltransferase,NAD ADP-Ribosyltransferase,NAD(+)-L-arginine ADP-D-ribosyltransferase,NAD-Agmatine ADP-Ribosyltransferase,NAD-Arginine ADP-Ribosyltransferase,NADP-ADPRTase,NADP-Arginine ADP-Ribosyltransferase,ADP Ribosyltransferase,ADP-Ribosyltransferase, NAD,ADP-Ribosyltransferase, NAD+,ADP-Ribosyltransferase, NAD-Agmatine,ADP-Ribosyltransferase, NAD-Arginine,ADP-Ribosyltransferase, NADP-Arginine,ADP-ribose Transferases, Mono,ADPribose Transferase, Mono,ADPribose Transferases, Mono,Mono ADP Ribosyltransferase,Mono ADP ribose Transferases,NAD ADP Ribosyltransferase,NAD Agmatine ADP Ribosyltransferase,NAD Arginine ADP Ribosyltransferase,NAD+ ADP Ribosyltransferase,NADP ADPRTase,NADP Arginine ADP Ribosyltransferase,Ribose Transferase, ADP,Ribose Transferases, ADP,Transferase, ADP Ribose,Transferase, ART,Transferase, Mono ADPribose,Transferases, ADP Ribose,Transferases, ART,Transferases, Mono ADP-ribose,Transferases, Mono ADPribose