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

Intestinal drug-resistant pathogens, e.g., Salmonella enterica subsp. enterica serovar Typhimurium (S. Tm) and enteropathogenic Escherichia coli (E. coli), 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 Lactobacillus plantarum (Lac) and Bifidobacterium animalis subsp. lactis (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 E. coli strain (Ecka), the co-assembly strongly reduced the viability of Ecka, leading to the increase in the ratio of probiotic to Ecka from 1.6 to 9.2. After oral administration of the co-assembly to the mice pre-colonized by Ecka, 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 S. Tm, the co-assembly remarkably recovered the mouse body weight, reduced intestine colonization of S. 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.