Intracellular activity of a membrane-active glycopeptide antibiotic against meticillin-resistant Staphylococcus aureus infection

• Studies were performed to assess the intracellular efficacy of the novel glycopeptide antibiotic Van-QC8.
• Van-QC8 displayed excellent intracellular activity against MRSA.
• Van-QC8 was internalised by macrophages via various endocytic pathways.

Staphylococcus aureus is a facultative intracellular pathogen and there are limited options for the treatment of severe intracellular bacterial infections. The membrane-active glycopeptide antibiotic Van-QC8 is a permanent positively charged lipophilic vancomycin analogue that demonstrates high activity against clinically relevant drug-resistant Gram-positive bacteria both in vitro and in vivo. In this study, the intracellular activity of Van-QC8 was evaluated against meticillin-resistant S. aureus (MRSA) infection in RAW macrophages. Furthermore, the mechanism of intracellular uptake of Van-QC8 was investigated. Van-QC8 showed time- and concentration-dependent bactericidal activity against intracellular MRSA. Van-QC8 displayed significantly higher intracellular activity compared with vancomycin and linezolid. Cellular uptake of Van-QC8 was found to be through clathrin-dependent and -independent and caveolin-dependent and -independent endocytic pathways. The findings of this study suggest that Van-QC8 could be translated clinically for the treatment of intracellular infections due to MRSA.