title: p-Sulfonato-calix[n]arenes inhibit staphylococcal bicomponent leukotoxins by supramolecular interactions.
abstract: PVL (Panton-Valentine leukocidin) and other Staphylococcus aureus β-stranded pore-forming toxins are important virulence factors involved in various pathologies that are often necrotizing. The present study characterized leukotoxin inhibition by selected SCns (p-sulfonato-calix[n]arenes): SC4, SC6 and SC8. These chemicals have no toxic effects on human erythrocytes or neutrophils, and some are able to inhibit both the activity of and the cell lysis by leukotoxins in a dose-dependent manner. Depending on the type of leukotoxins and SCns, flow cytometry revealed IC50 values of 6-22 μM for Ca2+ activation and of 2-50 μM for cell lysis. SCns were observed to affect membrane binding of class S proteins responsible for cell specificity. Electrospray MS and surface plasmon resonance established supramolecular interactions (1:1 stoichiometry) between SCns and class S proteins in solution, but not class F proteins. The membrane-binding affinity of S proteins was Kd=0.07-6.2 nM. The binding ability was completely abolished by SCns at different concentrations according to the number of benzenes (30-300 μM; SC8>SC6≫SC4). The inhibitory properties of SCns were also observed in vivo in a rabbit model of PVL-induced endophthalmitis. These calixarenes may represent new therapeutic avenues aimed at minimizing inflammatory reactions and necrosis due to certain virulence factors.
authors.affiliation: Université de Strasbourg, Fédération de Médecine Translationelle-Hôpitaux Universitaires de Strasbourg, Virulence bactérienne précoce (EA 7290) Institut de Bactériologie, 3 rue Koeberlé, 67 000 Strasbourg, France.
authors.forename: Benoît-Joseph
authors.initials: BJ
authors.lastname: Laventie
authors.forename: Cristina
authors.initials: C
authors.lastname: Potrich
authors.forename: Cédric
authors.initials: C
authors.lastname: Atmanène
authors.forename: Maher
authors.initials: M
authors.lastname: Saleh
authors.forename: Olivier
authors.initials: O
authors.lastname: Joubert
authors.forename: Gabriella
authors.initials: G
authors.lastname: Viero
authors.forename: Christoph
authors.initials: C
authors.lastname: Bachmeyer
authors.forename: Valeria
authors.initials: V
authors.lastname: Antonini
authors.forename: Ines
authors.initials: I
authors.lastname: Mancini
authors.forename: Sarah
authors.initials: S
authors.lastname: Cianferani-Sanglier
authors.forename: Daniel
authors.initials: D
authors.lastname: Keller
authors.forename: Didier A
authors.initials: DA
authors.lastname: Colin
authors.forename: Tristan
authors.initials: T
authors.lastname: Bourcier
authors.forename: Gregor
authors.initials: G
authors.lastname: Anderluh
authors.forename: Alain
authors.initials: A
authors.lastname: van Dorsselaer
authors.forename: Mauro
authors.initials: M
authors.lastname: Dalla Serra
authors.forename: Gilles
authors.initials: G
authors.lastname: Prévost
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047250:Calixarenes / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005098:Exotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D008954:Models, Biological; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000472:pathogenicity; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D005098:Exotoxins; D006460:Hemolysin Proteins; D046911:Macromolecular Substances; D010636:Phenols; D037521:Virulence Factors; C476540:calix(6)arene; C018579:leukotoxin; C511968:p-sulfonatocalix(4)arene; C524897:p-sulfonatocalix(8)arene; D047250:Calixarenes; D013108:Sphingomyelin Phosphodiesterase; C029878:hlb protein, Staphylococcus aureus