Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection.
J Antimicrob Chemother
; 71(5): 1245-51, 2016 May.
Article
in En
| MEDLINE
| ID: mdl-26895772
ABSTRACT
OBJECTIVES:
Ridinilazole (SMT19969) is a narrow-spectrum, non-absorbable antimicrobial with activity against Clostridium difficile undergoing clinical trials. The purpose of this study was to assess the pharmacological activity of ridinilazole and assess the effects on cell morphology.METHODS:
Antibiotic killing curves were performed using the epidemic C. difficile ribotype 027 strain, R20291, using supra-MIC (4× and 40×) and sub-MIC (0.125×, 0.25× and 0.5×) concentrations of ridinilazole. Following exposure, C. difficile cells were collected for cfu counts, toxin A and B production, and morphological changes using scanning electron and fluorescence microscopy. Human intestinal cells (Caco-2) were co-incubated with ridinilazole-treated C. difficile growth medium to determine the effects on host inflammatory response (IL-8).RESULTS:
Treatment at supra-MIC concentrations (4× and 40× MIC) of ridinilazole resulted in a significant reduction in vegetative cells over 72 h (4 log difference, Pâ<â0.01) compared with controls without inducing spore formation. These results correlated with a 75% decrease in toxin A production (Pâ<â0.05) and a 96% decrease in toxin B production (Pâ<â0.05). At sub-MIC levels (0.5× MIC), toxin A production was reduced by 91% (Pâ<â0.01) and toxin B production was reduced by 100% (Pâ<â0.001), which resulted in a 74% reduction in IL-8 release compared with controls (Pâ<â0.05). Sub-MIC (0.5×)-treated cells formed filamentous structures â¼10-fold longer than control cells. Following fluorescence labelling, the cell septum was not forming in sub-MIC-treated cells, yet the DNA was dividing.CONCLUSIONS:
Ridinilazole had robust killing effects on C. difficile that significantly reduced toxin production and attenuated the inflammatory response. Ridinilazole also elicited significant cell division effects suggesting a potential mechanism of action.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyridines
/
Bacterial Toxins
/
Benzimidazoles
/
Clostridioides difficile
/
Anti-Bacterial Agents
Limits:
Humans
Language:
En
Journal:
J Antimicrob Chemother
Year:
2016
Document type:
Article
Affiliation country:
United States