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

Turgeon Z, Jørgensen R, Visschedyk D, Edwards PR, Legree S, McGregor C, Fieldhouse RJ, Mangroo D, Schapira M, Merrill AR
Antimicrob Agents Chemother 55 983-91 (2011)
Cited: 25 times
EuropePMC logo PMID: 21135177

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.

Reviews - 3ny6 mentioned but not cited (2)

  1. The Father, Son and Cholix Toxin: The Third Member of the DT Group Mono-ADP-Ribosyltransferase Toxin Family. Lugo MR, Merrill AR. Toxins (Basel) 7 2757-2772 (2015)
  2. Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins. Lugo MR, Merrill AR. Toxins (Basel) 13 16 (2020)

Articles - 3ny6 mentioned but not cited (2)

  1. Newly discovered and characterized antivirulence compounds inhibit bacterial mono-ADP-ribosyltransferase toxins. Turgeon Z, Jørgensen R, Visschedyk D, Edwards PR, Legree S, McGregor C, Fieldhouse RJ, Mangroo D, Schapira M, Merrill AR. Antimicrob Agents Chemother 55 983-991 (2011)
  2. Ligand Selectivity between the ADP-Ribosylating Toxins: An Inverse-Docking Study for Multitarget Drug Discovery. Saenz-Méndez P, Eriksson M, Eriksson LA. ACS Omega 2 1710-1719 (2017)


Reviews citing this publication (6)

  1. Role of quorum sensing in bacterial infections. Castillo-Juárez I, Maeda T, Mandujano-Tinoco EA, Tomás M, Pérez-Eretza B, García-Contreras SJ, Wood TK, García-Contreras R. World J Clin Cases 3 575-598 (2015)
  2. Biology of Paenibacillus larvae, a deadly pathogen of honey bee larvae. Ebeling J, Knispel H, Hertlein G, Fünfhaus A, Genersch E. Appl Microbiol Biotechnol 100 7387-7395 (2016)
  3. Targeting bacterial toxins. Ivarsson ME, Leroux JC, Castagner B. Angew Chem Int Ed Engl 51 4024-4045 (2012)
  4. Targeting ADP-ribosylation as an antimicrobial strategy. Catara G, Corteggio A, Valente C, Grimaldi G, Palazzo L. Biochem Pharmacol 167 13-26 (2019)
  5. Exotoxin-Targeted Drug Modalities as Antibiotic Alternatives. Sakari M, Laisi A, Pulliainen AT. ACS Infect Dis 8 433-456 (2022)
  6. Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae. Ogura K, Yahiro K, Moss J. Toxins (Basel) 13 12 (2020)

Articles citing this publication (15)

  1. Antibiotic resistance-the need for global solutions. Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF, Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H, Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Ombaka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA, Coates A, Bergstrom R, Wright GD, Brown ED, Cars O. Lancet Infect Dis 13 1057-1098 (2013)
  2. Scabin, a Novel DNA-acting ADP-ribosyltransferase from Streptomyces scabies. Lyons B, Ravulapalli R, Lanoue J, Lugo MR, Dutta D, Carlin S, Merrill AR. J Biol Chem 291 11198-11215 (2016)
  3. C3larvin toxin, an ADP-ribosyltransferase from Paenibacillus larvae. Krska D, Ravulapalli R, Fieldhouse RJ, Lugo MR, Merrill AR. J Biol Chem 290 1639-1653 (2015)
  4. Certhrax toxin, an anthrax-related ADP-ribosyltransferase from Bacillus cereus. Visschedyk D, Rochon A, Tempel W, Dimov S, Park HW, Merrill AR. J Biol Chem 287 41089-41102 (2012)
  5. The 1.8 Å cholix toxin crystal structure in complex with NAD+ and evidence for a new kinetic model. Fieldhouse RJ, Jørgensen R, Lugo MR, Merrill AR. J Biol Chem 287 21176-21188 (2012)
  6. Characterization of an actin-targeting ADP-ribosyltransferase from Aeromonas hydrophila. Shniffer A, Visschedyk DD, Ravulapalli R, Suarez G, Turgeon ZJ, Petrie AA, Chopra AK, Merrill AR. J Biol Chem 287 37030-37041 (2012)
  7. Pocket analysis of the full-length cholix toxin. An assessment of the structure-dynamics of the apo catalytic domain. Lugo MR, Merrill AR. J Biomol Struct Dyn 33 2452-2468 (2015)
  8. A comparative structure-function analysis of active-site inhibitors of Vibrio cholerae cholix toxin. Lugo MR, Merrill AR. J Mol Recognit 28 539-552 (2015)
  9. Chemical Screens Identify Drugs that Enhance or Mitigate Cellular Responses to Antibody-Toxin Fusion Proteins. Antignani A, Mathews Griner L, Guha R, Simon N, Pasetto M, Keller J, Huang M, Angelus E, Pastan I, Ferrer M, FitzGerald DJ, Thomas CJ. PLoS One 11 e0161415 (2016)
  10. Several New Putative Bacterial ADP-Ribosyltransferase Toxins Are Revealed from In Silico Data Mining, Including the Novel Toxin Vorin, Encoded by the Fire Blight Pathogen Erwinia amylovora. Tremblay O, Thow Z, Merrill AR. Toxins (Basel) 12 E792 (2020)
  11. Crystal Structure of Exotoxin A from Aeromonas Pathogenic Species. Masuyer G. Toxins (Basel) 12 E397 (2020)
  12. Mapping the DNA-Binding Motif of Scabin Toxin, a Guanine Modifying Enzyme from Streptomyces scabies. Vatta M, Lyons B, Heney KA, Lidster T, Merrill AR. Toxins (Basel) 13 55 (2021)
  13. A Structural Approach to Anti-Virulence: A Discovery Pipeline. McCarthy M, Goncalves M, Powell H, Morey B, Turner M, Merrill AR. Microorganisms 9 2514 (2021)
  14. Anti-Virulence Strategy against the Honey Bee Pathogenic Bacterium Paenibacillus larvae via Small Molecule Inhibitors of the Bacterial Toxin Plx2A. Ebeling J, Pieper F, Göbel J, Knispel H, McCarthy M, Goncalves M, Turner M, Merrill AR, Genersch E. Toxins (Basel) 13 607 (2021)
  15. The DarT/DarG Toxin-Antitoxin ADP-Ribosylation System as a Novel Target for a Rational Design of Innovative Antimicrobial Strategies. Catara G, Caggiano R, Palazzo L. Pathogens 12 240 (2023)


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