title: Effects of ciprofloxacin on the expression and production of exotoxins by Clostridium difficile.
abstract: Hypervirulent BI/NAP1/027 strains of Clostridium difficile have been associated with increased mortality of C. difficile infection (CDI). The emergence of highly fluoroquinolone (FLQ)-resistant BI/NAP1/027 strains suggests that FLQ exposure may be a risk factor for CDI development. However, the mechanism for this is not clear. We compared the effects of subinhibitory concentrations of ciprofloxacin on Toxin A and B gene expression and protein production in recent (strain 039) and historical (strain 5325) BI/NAP1/027 clinical isolates with high- and low-level ciprofloxacin resistance, respectively. In the highly ciprofloxacin-resistant isolate (strain 039), ciprofloxacin significantly and dose-dependently increased Toxin A gene expression and shifted its expression to earlier in its growth cycle; TcdB gene expression also increased but was less sensitive to low-dose ciprofloxacin. Maximal Toxin A/B production (4 ng ml(-1)) was increased twofold and occurred significantly earlier than in the untreated control. In strain 5325, ciprofloxacin at 0.25×MIC markedly increased both tcdA and tcdB expression but their temporal dynamics were unchanged. Maximal toxin production (250 ng ml(-1)) was reduced approximately threefold compared with that of the untreated control. These results demonstrate significant differences in ciprofloxacin-induced toxin gene expression and protein production among BI/NAP1/027 isolates, and offer a new paradigm for FLQ-associated CDI caused by recent, highly antibiotic-resistant strains.
authors: Department of Veterans Affairs Medical Center, Boise, ID, USA.
authors: Michael John
authors: MJ
authors: Aldape
authors: Department of Veterans Affairs Medical Center, Boise, ID, USA.
authors: Aaron Eugene
authors: AE
authors: Packham
authors: Department of Veterans Affairs Medical Center, Boise, ID, USA.
authors: Drew William
authors: DW
authors: Nute
authors: University of Washington School of Medicine, Seattle, WA, USA.|Department of Veterans Affairs Medical Center, Boise, ID, USA.
authors: Amy Evelyn
authors: AE
authors: Bryant
authors: University of Washington School of Medicine, Seattle, WA, USA.|Department of Veterans Affairs Medical Center, Boise, ID, USA.
authors: Dennis Leroy
authors: DL
authors: Stevens
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D002939:Ciprofloxacin / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000378:metabolism; D004768:Enterotoxins / Q000235:genetics / Q000378:metabolism; D005098:Exotoxins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects*; D008826:Microbial Sensitivity Tests
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D005098:Exotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D002939:Ciprofloxacin