Tolevamer, an anionic polymer, neutralizes toxins produced by the BI/027 strains of Clostridium difficile.
Clostridium difficile-associated diarrhea (CDAD) is caused by the toxins the organism produces when it overgrows in the colon as a consequence of antibiotic depletion of normal flora. Conventional antibiotic treatment of CDAD increases the likelihood of recurrent disease by again suppressing normal bacterial flora. Tolevamer, a novel toxin-binding polymer, was developed to ameliorate the disease without adversely affecting normal flora. In the current study, tolevamer was tested for its ability to neutralize clostridial toxins produced by the epidemic BI/027 strains, thereby preventing toxin-mediated tissue culture cell rounding. The titers of toxin-containing C. difficile culture supernatants were determined using confluent cell monolayers, and then the supernatants were used in assays containing dilutions of tolevamer to determine the lowest concentration of tolevamer that prevented > or =90% cytotoxicity. Tolevamer neutralized toxins in the supernatants of all C. difficile strains tested. Specific antibodies against the large clostridial toxins TcdA and TcdB also neutralized the cytopathic effect, suggesting that tolevamer is specifically neutralizing these toxins and that the binary toxin (whose genes are carried by the BI/027 strains) is not a significant source of cytopathology against tissue culture cells in vitro.
Hinkson
Paul L
PL
Genzyme Drug and Biomaterial Research and Development, 153 Second Avenue, Waltham, Massachusetts 02451, USA.
Dinardo
Carol
C
DeCiero
Daniel
D
Klinger
Jeffrey D
JD
Barker
Robert H
RH
D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D001427:Bacterial Toxins / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D016360:Clostridioides difficile / Q000378:metabolism / Q000472:pathogenicity*; D004761:Enterocolitis, Pseudomembranous / Q000382:microbiology; D004768:Enterotoxins / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D009500:Neutralization Tests; D011108:Polymers / Q000378:metabolism* / Q000494:pharmacology*; D013451:Sulfonic Acids; D014709:Vero Cells
D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D011108:Polymers; D013451:Sulfonic Acids; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; C077114:styrenesulfonic acid polymer