Contact
    Start Publications Antibiotic-in-Cyclodextrin-in-Liposomes: Formulation ...
    ←  Publication Finder
    KSV NIMA

    Antibiotic-in-Cyclodextrin-in-Liposomes: Formulation Development and Interactions with Model Bacterial Membranes

    Year: 2020

    Journal: Mol. Pharm., Volume 17, JUL 6, page 2354–2369

    Authors: Vandera, KKA; Picconi, P; Valero, M; Gonzalez-Gaitano, G; Woods, A; Zain, NMM; Bruce, KD; Clifton, LA; Skoda, MWA; Rahman, KM; Harvey, RD; Dreiss, CA

    Organizations: ISIS STFC, Didcot, U.K. [1710319]

    Keywords: antimicrobial resistance; antibiotic formulation; membrane fusion; Langmuir monolayers; neutron reflectivity; asymmetric bilayer

    Gram-negative bacteria possess numerous defenses against antibiotics, due to the intrinsic permeability barrier of their outer membrane (OM), explaining the recalcitrance of some common and life-threatening infections. We report the formulation of a new drug, PPA148, which shows promising activity against all Gram-negative bacteria included in the ESKAPEE pathogens. PPA148 was solubilized by inclusion complexation with cyclodextrin followed by encapsulation in liposomes. The complex and liposomal formulation presented increased activity against E. coli compared to the pure drug when assessed with the Kirby Bauer assay. The novel formulation containing 1 mu g PPA148 reached similar efficacy levels equivalent to those of 30 mu g of pure rifampicin. A range of biophysical techniques was used to explore the mechanism of drug uptake. Langmuir trough (LT) and neutron reflectivity (NR) techniques were employed to monitor the interactions between the drug and the formulation with model membranes. We found evidence for liposome fusion with the model Gram-negative outer membrane and for cyclodextrins acting as inner membrane (IM) permeation enhancers without presenting intrinsic antimicrobial activity. An antibiotic-in-cyclodextrin-in-liposomes (ACL) formulation was developed, which targets both the bacterial OM and IM, and offers promise as a means to breach the Gram-negative cell envelope.
    View publication