Photochemical internalization enhances cytosolic release of antibiotic and increases its efficacy against staphylococcal infection.

Abstract

Bacterial pathogens such as Staphylococcus aureus and Staphylococcus epidermidis can survive in different types of cells including professional phagocytes, causing intracellular infections. Antibiotic treatment of intracellular infections is often unsuccessful due to the low efficacy of most antibiotics inside cells. Therefore, novel techniques which can improve intracellular activity of antibiotics are urgently needed. We aimed to use photochemical internalization (PCI) to enhance cytosolic release of antibiotics from endocytic vesicles after internalization. Our results show that PCI indeed caused cytosolic release of gentamicin and significantly increased its efficacy against S. epidermidis in vitro in mouse macrophages. Upon illumination for 15 min, the killing of intracellular S. epidermidis in RAW 264.7 cells by 10 or 30 μg/ml gentamicin was increased to 1 or 3 CFU log, respectively, owing to the use of PCI, whereas no killing by gentamicin only without PCI was observed. Moreover, survival of S. aureus-infected zebrafish embryos was significantly improved by treatment with PCI-gentamicin. PCI improved the therapeutic efficacy of gentamicin at a dose of 0.1 ng per embryo to a level similar to that of a dose of 0.4 ng per embryo, indicating that PCI can lower the antibiotic dose required for treating (intracellular) staphylococcal infection. Thus, the present study shows that PCI is a promising novel approach to enhance the intracellular efficacy of antibiotics via cytosolic release, allowing them to reach intracellular bacteria. This will expand their therapeutic window and will increase the numbers of antibiotics which can be used for treatment of intracellular infections.

• Authors: Xiaolin Zhang, Leonie de Boer, Laura Heiliegers, Sandra Man-Bovenkerk, Pål Kristian Selbo, Jan W Drijfhout, Anders Høgset, Sebastian A J Zaat
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 283 Pg. 214-222 (08 10 2018) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 29883696 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Gentamicins
• Photosensitizing Agents
• Porphyrins
• di(4-sulfonatophenyl)diphenylporphine

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage)
• Cytosol (metabolism)
• Embryo, Nonmammalian
• Gentamicins (administration & dosage)
• Light
• Mice
• Photosensitizing Agents (administration & dosage)
• Porphyrins (administration & dosage)
• RAW 264.7 Cells
• Staphylococcal Infections (drug therapy)
• Staphylococcus aureus (drug effects)
• Staphylococcus epidermidis (drug effects)
• Zebrafish