title: Intracellular activity of a membrane-active glycopeptide antibiotic against meticillin-resistant Staphylococcus aureus infection.
abstract: 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.
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, Karnataka, India.
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Yarlagadda
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, Karnataka, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Samaddar
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, Karnataka, India. Electronic address: jayanta@jncasr.ac.in.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D000067996:RAW 264.7 Cells; D014640:Vancomycin / Q000031:analogs & derivatives*
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D014640:Vancomycin
keywords: Glycopeptides; Intracellular activity; MRSA; Membrane-active antibiotic; Meticillin-resistant Staphylococcus aureus