Probing the interaction of liposome delivery systems with Gram negative bacterial cell envelopes: a comprehensive investigative approach

People involved

Dr. Yixuan Yan (postdoc funded by the PRC), University of Birmingham, UK

Prof. Jayne Lawrence, University of Manchester, UK

Dr. Tim Overton, University of Birmingham, UK

Abstract

Antimicrobial resistance, often referred to as the ‘silent pandemic’, constitutes a major threat to global public health, with antimicrobial-resistant infections predicted to cause 10 million deaths worldwide by 2050.1) The increasing level of drug resistance in Gram-negative bacteria is of particular concern—this is evident from the World Health Organization list of priority resistant bacteria, on which all organisms designated as being of critical concern are Gram-negatives.2) Gram negative resistance is mediated in part by their complex double-membrane envelope structure, which presents a formidable barrier to the cellular entry and action of anti-infectives. As a further problem, the shrinking pool of effective antibiotics is currently not being refilled by new treatment options.3) Strategic development of delivery systems designed to interact with the Gram-negative bacterial envelope barrier in particular has therefore become crucial for the efficient delivery of antibiotics to bacterial cell interiors, as resistance continues to evolve, and new treatment options remain scarce.

This project will comprehensively characterize the ability of a panel of liposome formulations to interact with different Gram-negative bacterial cell envelope structures, using a range of biophysical and microbiological approaches. In doing so, the proposed work will allow for direct comparison of the ability of a range of liposome formulation approaches to interact with the Gram-negative bacterial cell envelope and will provide much-needed insights into the unexplored potential of ‘bacteriomimetic’ liposomes as cell envelope-interacting delivery systems. A multi-pronged characterization approach utilizing Langmuir monolayers, flow cytometry and super-resolution microscopy will generate comprehensive model membrane-based, bacterial population-representative and single organism-focused data on the interaction of liposome formulations with a variety of Gram-negative bacterial envelope structures. Preliminary, relative efficacy data will also be generated.

Benefit for the community

The proposed work will contribute to phospholipid research by offering insight into the existence of a universal ‘best’ vs. target organism-specific ‘optimal’ liposome formulation strategy for promoting cell envelope interaction. It will also contribute towards collective knowledge of the utility of emerging, super-resolution microscopy techniques for characterizing lipid-based delivery system interactions with single cells, and their potential future role in the informed development of cell-interacting lipid-based drug delivery systems.

Visit the supervisors lab

Contact to Sarah Gordon.