TY - JOUR
T1 - Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles
AU - Jiang, Lai
AU - Greene, Michelle K.
AU - Insua, José Luis
AU - Sa-Pessoa, Joana
AU - Small, Donna M.
AU - Smyth, Peter
AU - McCann, Aidan
AU - Cogo, Francesco
AU - Bengoechea, Jose A.
AU - Taggart, Clifford C.
AU - Scott, Christopher J.
PY - 2018/4/25
Y1 - 2018/4/25
N2 - Klebsiella pneumoniae is a foremost gram-negative pathogen that can induce life-threatening nosocomial pulmonary infections. Although it can be phagocytosed successfully by lung resident macrophages, this pathogen remains viable within vacuolar compartments, resulting in chronic infection and limiting therapeutic treatment with antibiotics. In this study, we aimed to generate and evaluate a cell-penetrant antibiotic poly( lactide- co- glycolide) (PLGA)-based formulation that could successfully treat intracellular K. pneumoniae infection. Screening of formulation conditions allowed the generation of high drug entrapment nanoparticles through a water-in-oil-in-water approach. We demonstrated the therapeutic usefulness of these gentamicin-loaded nanoparticles (GNPs), showing their ability to improve survival and provide extended prophylactic protection towards K. pneumoniae using a Galleria mellonella infection model. We subsequently showed that the GNPs could be phagocytosed by K. pneumoniae infected macrophages, and significantly reduce the viability of the intracellular bacteria without further stimulation of pro-inflammatory or pro-apoptotic effects on the macrophages. Taken together, these results clearly show the potential to use antibiotic loaded NPs to treat intracellular K. pneumoniae infection, reducing bacterial viability without concomitant stimulation of inflammatory or pyroptotic pathways in the treated cells.
AB - Klebsiella pneumoniae is a foremost gram-negative pathogen that can induce life-threatening nosocomial pulmonary infections. Although it can be phagocytosed successfully by lung resident macrophages, this pathogen remains viable within vacuolar compartments, resulting in chronic infection and limiting therapeutic treatment with antibiotics. In this study, we aimed to generate and evaluate a cell-penetrant antibiotic poly( lactide- co- glycolide) (PLGA)-based formulation that could successfully treat intracellular K. pneumoniae infection. Screening of formulation conditions allowed the generation of high drug entrapment nanoparticles through a water-in-oil-in-water approach. We demonstrated the therapeutic usefulness of these gentamicin-loaded nanoparticles (GNPs), showing their ability to improve survival and provide extended prophylactic protection towards K. pneumoniae using a Galleria mellonella infection model. We subsequently showed that the GNPs could be phagocytosed by K. pneumoniae infected macrophages, and significantly reduce the viability of the intracellular bacteria without further stimulation of pro-inflammatory or pro-apoptotic effects on the macrophages. Taken together, these results clearly show the potential to use antibiotic loaded NPs to treat intracellular K. pneumoniae infection, reducing bacterial viability without concomitant stimulation of inflammatory or pyroptotic pathways in the treated cells.
U2 - 10.1016/j.jconrel.2018.04.040
DO - 10.1016/j.jconrel.2018.04.040
M3 - Article
VL - 279
SP - 316
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -