Gram‐Negative Bacteria Targeting Mediated by Carbohydrate–Carbohydrate Interactions Induced by Surface‐Modified Nanoparticles

Abstract Antibiotic resistant pathogens are a modern threat to the human health. As a worldwide spreading problem, there is an urgency for new strategies to minimize antibiotic resistance, particularly the super‐resistant strains. Here, the efficient design of carbohydrate‐coated silica nanoparticles is reported which specifically target Gram‐negative bacteria cells. The system is functionalized with gluconamide moieties and demonstrates increased binding ability to the bacterial membrane, enabling controlled drug delivery onto the pathogen wall. In addition, the high stability of the nanoparticles in biological media and the lack of non‐specific protein adhesion are engendered by such functionalization, which also demonstrates low cytotoxicity and hemolytic activity prevention. Local interaction between nanoparticles and the bacterium membrane is experimentally accessed at the biomolecular level unveiling a short‐range chemical connection. Atomistic molecular dynamics simulations depict the rapid penetration of gluconamide in the lipopolysaccharide region of the bacterial outer membrane, corroborating the experimental findings. Thus, this novel outer membrane‐targeting platform provides a new strategy to reduce drug intake and, hence, minimize bacterial resistance.