Abstract
Preservation and augmentation of existing antimicrobials is crucial in combating antimicrobial resistance. Gram-positive bacteria, exemplified by Staphylococcus aureus, are among the most common human bacterial pathogens, with methicillin-resistant S. aureus (MRSA) now established globally. Daptomycin is a last-line anti-staphylococcal antimicrobial that uniquely targets the bacterial membrane with bactericidal effects. Here, we developed lipid-based nanoparticles, namely cubosomes, to encapsulate daptomycin for targeted delivery via lipid-mediated interactions. Daptomycin-loaded cubosomes synergistically killed 14 clinical MRSA isolates in vitro compared with daptomycin or cubosomes alone. This synergy between daptomycin and cubosome was mediated by cubosomes docking on the S. aureus cell surface, releasing daptomycin for membrane extraction and penetration, followed by lipid cubosome infusion into S. aureus membranes. Using a murine septicemia model, daptomycin-loaded cubosomes significantly reduced the organ bacterial burden of MRSA. Together, these data showed that multifunctional lipid nanocarriers can potentiate the bactericidal activity of daptomycin using a membrane-targeted trojan-horse-like mechanism.