title: Self-assembled squalenoylated penicillin bioconjugates: an original approach for the treatment of intracellular infections.
abstract: We describe here new nanoparticles based on the bioconjugation of penicillin G to squalene in order to overcome severe intracellular infections by pathogen bacteria whose mechanism of resistance arises from the poor intracellular diffusion of several antibiotics. Two different squalene-penicillin G conjugates were synthesized (pH-sensitive and pH-insensitive), and their self-assembly as nanoparticles was investigated through morphology and stability studies. These nanoparticles had a size of 140 ± 10 nm (polydispersity index of 0.1) and a negative charge, and they did not display any supramolecular organization. Furthermore, they were found stable in water and in different culture medium. The cellular uptake and localization of these fluorescently labeled nanoparticles were explored on the macrophage cell line J774 by flow cytometry and confocal microscopy analysis. The squalenoylated nanoparticles were found to be cell internalized through clathrin-dependent and -independent endocytic pathways. Moreover, they induced an improved intracellular antibacterial activity on the facultative intracellular pathogen S. aureus, compared with free penicillin G, despite the absence of co-localization between the bacteria and the nanoparticles in the cells. This study suggests that the bioconjugation of an antibiotic to a squalene template could be a valuable approach for overcoming the antibiotic resistance due to intracellular bacterial infections.
authors.affiliation: Faculty of Pharmacy, UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sémiramoth
authors.forename: Chiara
authors.initials: C
authors.lastname: Di Meo
authors.forename: Fatima
authors.initials: F
authors.lastname: Zouhiri
authors.forename: Fatouma
authors.initials: F
authors.lastname: Saïd-Hassane
authors.forename: Sabrina
authors.initials: S
authors.lastname: Valetti
authors.forename: Roseline
authors.initials: R
authors.lastname: Gorges
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Poupaert
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chollet-Martin
authors.forename: Didier
authors.initials: D
authors.lastname: Desmaële
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Gref
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D001424:Bacterial Infections / Q000188:drug therapy*; D006801:Humans; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D010406:Penicillins / Q000737:chemistry* / Q000627:therapeutic use; D013185:Squalene / Q000737:chemistry*
chemical_list: D010406:Penicillins; D013185:Squalene