Daptomycin-Loaded Nanocarriers Facilitate Synergistic Killing of Methicillin-Resistant Staphylococcus aureus via
Jhih-Hang Jiang1,2,3, Chia Xin Lim4, Xiangfeng Lai5
1Infection Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Victoria, Australia.
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.
Insights
Novel cubosomes loaded with daptomycin enhance killing of methicillin-resistant Staphylococcus aureus (MRSA). This lipid nanoparticle delivery system potentiates daptomycin
Area of Science:
- Nanotechnology
- Microbiology
- Pharmacology
Background:
- Antimicrobial resistance (AMR) necessitates novel therapeutic strategies.
- Gram-positive bacteria, such as Staphylococcus aureus (including MRSA), pose significant global health threats.
- Daptomycin is a critical last-line antibiotic for staphylococcal infections, targeting bacterial membranes.
Purpose of the Study:
- To develop lipid-based nanoparticles (cubosomes) for targeted daptomycin delivery.
- To investigate the synergistic antimicrobial activity of daptomycin-loaded cubosomes against MRSA.
- To elucidate the mechanism of action for this enhanced therapeutic approach.
Main Methods:
- Development of daptomycin-encapsulated cubosomes.
- In vitro testing against 14 clinical MRSA isolates.
- In vivo evaluation using a murine septicemia model.
Main Results:
- Daptomycin-loaded cubosomes demonstrated synergistic bactericidal effects against MRSA in vitro.
- The mechanism involves cubosome docking, daptomycin release, membrane penetration, and lipid infusion.
- Significant reduction in MRSA bacterial burden in murine septicemia models.
Conclusions:
- Multifunctional lipid nanocarriers (cubosomes) can potentiate daptomycin's activity.
- A "Trojan horse"-like mechanism enhances daptomycin delivery and efficacy.
- Cubosomes represent a promising strategy for combating MRSA infections.
