Artificial polysaccharide-binding protein mediates co-assembly of nanodrug and probiotics against drug-resistant infectious enteritis

Intestinal drug-resistant pathogens, e.g., <i>Salmonella</i> enterica subsp. <i>enterica</i> serovar Typhimurium (<i>S</i>. Tm) and enteropathogenic <i>Escherichia coli (E. coli)</i>, frequently cause life-threatening infectious enteritis. Probiotic-based therapy is a promising way to eliminate drug-resistant pathogens for treatment of infectious enteritis, but its colonizing and therapeutic efficacy after oral administration are limited. Here, we developed a facile therapeutic agent to treat infectious enteritis by co-assembly of the peptide nanodrug melittin-loaded MSN grafted by polysaccharide-binding protein (MMPB) with the famous probiotic bacteria <i>Lactobacillus plantarum</i> (Lac) and <i>Bifidobacterium animalis</i> subsp. <i>lactis</i> (Bif). The nanodrug was composed of the antimicrobial peptide melittin and mesoporous silica nanoparticles exposing the artificial polysaccharide-binding protein. Owing to presence of the artificial protein on the MMPB surface, the nanodrug strongly bound and cross-linked the probiotic cells, forming the Lac+Bif+MMPB co-assembly. During co-incubation with the kanamycin-resistant <i>E. coli</i> strain (<i>Ecka</i>), the co-assembly strongly reduced the viability of <i>Ecka</i>, leading to the increase in the ratio of probiotic to <i>Ecka</i> from 1.6 to 9.2. After oral administration of the co-assembly to the mice pre-colonized by <i>Ecka</i>, Lac+Bif+MMPB almost eliminated the kanamycin-resistant gene in the intestine, and led to 2-3-fold higher levels of the probiotic cells than the nanodrug MMPB or the combined probiotics Lac+Bif. More importantly, in the mice suffering from enteritis caused by drug-resistant <i>S</i>. Tm, the co-assembly remarkably recovered the mouse body weight, reduced intestine colonization of <i>S</i>. Tm cells, and decreased the levels of pro-inflammatory cytokines in both serum and colons. This study realized the synthetic biology technique-mediated abiotic/biotic co-assembly for efficient treating infectious enteritis induced by drug-resistant pathogens.