Polysaccharide‐Targeting Lipid Nanoparticles to Kill Gram‐Negative Bacteria

Abstract

AbstractThe rapid increase and spread of Gram‐negative bacteria resistant to many or all existing treatments threaten a return to the preantibiotic era. The presence of bacterial polysaccharides that impede the penetration of many antimicrobials and protect them from the innate immune system contributes to resistance and pathogenicity. No currently approved antibiotics target the polysaccharide regions of microbes. Here, describe monolaurin‐based niosomes, the first lipid nanoparticles that can eliminate bacterial polysaccharides from hypervirulentKlebsiella pneumoniae, are described. Their combination with polymyxin B shows no cytotoxicityin vitroand is highly effective in combatingK. pneumoniaeinfectionin vivo. Comprehensive mechanistic studies have revealed that antimicrobial activity proceeds via a multimodal mechanism. Initially, lipid nanoparticles disrupt polysaccharides, then outer and inner membranes are destabilized and destroyed by polymyxin B, resulting in synergistic cell lysis. This novel lipidic nanoparticle system shows tremendous promise as a highly effective antimicrobial treatment targeting multidrug‐resistant Gram‐negative pathogens.