Abstract
Current antibiotic treatments fail to eliminate the Clostridium difficile (C. difficile) spores and induce dysbiosis and intestinal inflammation via off-target effect, which causes refractory C. difficile infection raise an unmet need for a spore-specific antimicrobial treatment. We developed a sporicidal and antimicrobial vancomycin-loaded spore-targeting iron oxide nanoparticle (van-IONP) that selectively binds to C. difficile spores. Cryo-electron microscopy showed that vancomycin-loaded nanoparticles can target and completely cover spore surfaces. They not only successfully delayed the germination of the spores but also inhibited ∼50% of vegetative cell outgrowth after 48 h of incubation. The van-IONPs also inhibited the interaction of spores with HT-29 intestinal mucosal cells in vitro. In a murine model of C. difficile infection, the van-IONP significantly protected the mice from infected by C. difficile infection, reducing intestinal inflammation, and facilitated superior mucosal viability compared with equal doses of free vancomycin. This dual-function targeted delivery therapy showed advantages over traditional therapeutics in treating C. difficile infection.
Highlights
Clostridium difficile (C. difficile) infection (CDI), the clinical manifestations of which are usually dangerous and fatal
We developed vancomycin-loaded Fe3−δO4 magnetite nanoparticles to target and inhibit both the vegetative cells and the spores of C. difficile
Colony-forming unit (CFU) assay showed no significant inhibition of spore germination 48 h after they had been treated with vancomycin at 18 mg/mL concentration (Figure 1B)
Summary
Clostridium difficile (C. difficile) infection (CDI), the clinical manifestations of which (e.g., severe or bloody diarrhea, PMC, and toxic megacolon) are usually dangerous and fatal. CDI is one of the most common healthcare-acquired infections associated with the rising use of antibiotics (Johnson et al, 1999). C. difficile, transmitted in humans through the fecal-oral route, is an anaerobic Gram-positive, spore-forming bacillus that produces toxins, including TcdA and TcdB, two large-molecules that damage intestinal mucosa and induce. Targeted Therapy for C. difficile Infection neutrophilic colitis and pseudomembranous colitis (PMC) (Leffler and Lamont, 2015). More-virulent strains like BI/NAP1/027, an additional binary toxin composed of two subunits CdtA and CdtB, which increase the adherence of bacteria to the intestinal mucosa (Gerding et al, 2014)
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