Abstract
Bacterial invasion into eukaryotic cells and the establishment of intracellular infection has proven to be an effective means of resisting antibiotic action, as anti-infective agents commonly exhibit a poor permeability across the host cell membrane. Encapsulation of anti-infectives into nanoscaled delivery systems, such as liposomes, is shown to result in an enhancement of intracellular delivery. The aim of the current work is, therefore, to formulate colistin, a poorly permeable anti-infective, into liposomes suitable for oral delivery, and to functionalize these carriers with a bacteria-derived invasive moiety to enhance their intracellular delivery. Different combinations of phospholipids and cholesterol are explored to optimize liposomal drug encapsulation and stability in biorelevant media. These liposomes are then surface-functionalized with extracellular adherence protein (Eap), derived from Staphylococcus aureus. Treatment of HEp-2 and Caco-2 cells infected with Salmonella enterica using colistin-containing, Eap-functionalized liposomes resulted in a significant reduction of intracellular bacteria, in comparison to treatment with nonfunctionalized liposomes as well as colistin alone. This indicates that such bio-invasive carriers are able to facilitate intracellular delivery of colistin, as necessary for intracellular anti-infective activity. The developed Eap-functionalized liposomes, therefore, present a promising strategy for improving the therapy of intracellular infections.
Highlights
Different combinations of phospholipids and cholesterol are explored to optimize liposomal drug encapsulation and stability in biorelevant media. These liposomes are surface-functionalized with extracellular due to a significant increase in antimicrobial resistance[2,3] combined with recent reports of toxic and metabolic side effects resulting from the use of fluoroquinolones[4] (FDA Report, Drug Safety and Availability, 7 October 2018), there is adherence protein (Eap), derived from Staphylococcus aureus
HEp-2 and Caco-2 cells infected with Salmonella enterica using colistin-containing, extracellular adherence protein (Eap)-functionalized liposomes resulted in a significant reduction of intracellular bacteria, in comparison to treatment with nonfunctionalized liposomes as well as colistin alone
By facilitating intracellularly delivery of their anti-infective cargo, i.e., colistin, which is normally unable to permeate across cellular membranes, a substantial killing of the enteroinvasive bacterium S. enterica in epithelial cells was achieved
Summary
Different combinations of phospholipids and cholesterol are explored to optimize liposomal drug encapsulation and stability in biorelevant media These liposomes are surface-functionalized with extracellular due to a significant increase in antimicrobial resistance[2,3] combined with recent reports of toxic and metabolic side effects resulting from the use of fluoroquinolones[4] (FDA Report, Drug Safety and Availability, 7 October 2018), there is adherence protein (Eap), derived from Staphylococcus aureus. HEp-2 and Caco-2 cells infected with Salmonella enterica using colistin-containing, Eap-functionalized liposomes resulted in a significant reduction of intracellular bacteria, in comparison to treatment with nonfunctionalized liposomes as well as colistin alone This indicates that such bio-invasive carriers are able to options. Need for new therapies has seen it re-emerge as a “last resort” treatment option for Gramnegative MDR infections.[6,7] Its use is currently restricted to parenteral administration
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