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Molecular Mechanisms of Cationic Fusogenic Liposome Interactions with Bacterial Envelopes.

Published version
Peer-reviewed

Repository DOI


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Authors

Scheeder, Anna 
Brockhoff, Marius 
Ward, Edward N 
Kaminski Schierle, Gabriele S  ORCID logo  https://orcid.org/0000-0002-1843-2202

Abstract

Although fusogenic liposomes offer a promising approach for the delivery of antibiotic payloads across the cell envelope of Gram-negative bacteria, there is still a limited understanding of the individual nanocarrier interactions with the bacterial target. Using super-resolution microscopy, we characterize the interaction dynamics of positively charged fusogenic liposomes with Gram-negative (Escherichia coli) and Gram-positive (Bacillus subtilis) bacteria. The liposomes merge with the outer membrane (OM) of Gram-negative bacteria, while attachment or lipid internalization is observed in Gram-positive cells. Employing total internal reflection fluorescence microscopy, we demonstrated liposome fusion with model supported lipid bilayers. For whole E. coli cells, however, we observed heterogeneous membrane integrations, primarily involving liposome attachment and hemifusion events. With increasing lipopolysaccharide length, the likelihood of full-fusion events was reduced. The integration of artificial lipids into the OM of Gram-negative cells led to membrane destabilization, resulting in decreased bacterial vitality, membrane detachment, and improved codelivery of vancomycin─an effective antibiotic against Gram-positive cells. These findings provide significant insights into the interactions of individual nanocarriers with bacterial envelopes at the single-cell level, uncovering effects that would be missed in bulk measurements. This highlights the importance of conducting single-particle and single-cell investigations to assess the performance of next-generation drug delivery platforms.

Description

Publication status: Published

Keywords

Liposomes, Escherichia coli, Anti-Bacterial Agents, Drug Delivery Systems, Cell Membrane, Gram-Negative Bacteria

Journal Title

J Am Chem Soc

Conference Name

Journal ISSN

0002-7863
1520-5126

Volume Title

145

Publisher

American Chemical Society (ACS)
Sponsorship
EPSRC (2519612)
Engineering and Physical Sciences Research Council (EP/L015889/1)
Engineering and Physical Sciences Research Council (EP/H018301/1)
Wellcome Trust (089703/Z/09/Z)
Medical Research Council (MR/K02292X/1)
Royal Society (URF\R1\221795 and RF\ERE\22103)
Michael J. Fox Foundation (MJFF) (16238)
Wellcome Trust (065807/Z/01/Z)
Wellcome Trust (203249/Z/16/Z)
National Biofilms Innovation Centre (NBIC) (via University of Southampton) (BB/R012415/1 - 03PoC20-105)
Medical Research Council (MR/K015850/1)
Engineering and Physical Sciences Research Council (EP/S022953/1)