title: An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance.
abstract: The "Golden era" of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55-63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells.
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Nadia
authors: N
authors: Abed
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Fatouma
authors: F
authors: Saïd-Hassane
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Fatima
authors: F
authors: Zouhiri
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Julie
authors: J
authors: Mougin
authors: Faculty of Pharmacy, INSERM IFR 141 University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Valérie
authors: V
authors: Nicolas
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Didier
authors: D
authors: Desmaële
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Ruxandra
authors: R
authors: Gref
authors: Faculty of Pharmacy, Institut Galien UMR CNRS 8612, University of Paris-Sud XI, 5 Rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
authors: Patrick
authors: P
authors: Couvreur
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D016503:Drug Delivery Systems; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D053758:Nanoparticles / Q000648:ultrastructure; D010400:Penicillin G / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D047090:beta-Lactams; D010400:Penicillin G