Nanoprecision in antibiotic delivery using targeted nanoparticles

Gram-negative bacterial species, including E. coli, are major causes of infectious diseases worldwide and account for all organisms in the “critical” category of the WHO list of antibiotic-resistant “priority pathogens”. These bacteria are intrinsically drug-resistant due to the presence of an impermeable outer membrane. The design of novel antibiotics with activity against Gram-negative bacteria can be challenging due to the drug’s size and hydrophobicity properties for crossing the membrane and accessing intracellular targets. Most antibiotics work by entering bacterial cells and interacting with specific targets to kill or inhibit cell growth. However Gram-negative bacteria are also especially adept at limiting intracellular antibiotic accumulation with a suite of efflux pumps that export a broad range of antimicrobials. A multi-targeted approach of local delivery is necessary to increase efficiency of drug localisation and effective drug activity which will lead in limiting drug dose and new methods of therapies.

Nanoscale materials are attractive vehicles for the delivery of therapeutic agents with wide chemical versatility which provides potential to overcome multi-drug resistance mechanisms. Recently we have developed functional nanoparticles for targeted therapeutic properties based on either functional modification of their surface to allow membrane penetration. or internal modification of the structural framework to encapsulate drugs. This project will investigate novel nanoparticle designs using supramolecular chemistry principles for molecular encapsulation in the nanoparticle framework of drugs and inhibitors of efflux pumps but also bioinorganic chemistry approaches to intervene with receptors present in bacterial membranes to allow both efficient cross of the nano-platform in the bacterial cell, limitation of drug exportation and efficient drug delivery. The project builds on recent results on drug encapsulation and release.

Hypothesis: In this project we will develop a set of nanoparticles with iron siderophores that target specific proteins in the bacterial cell membrane to increase the uptake of antibiotics inside the cell. We will design nanoparticle networks incorporating inhibitors to efflux pumps to limit antibiotic expulsion. We will use supramolecular recognition principles to select efficient pairs of drugs and inhibitors.

Methods: The project includes molecular synthesis of ligands and metal complexes, nanoparticle modification and characterisation as well as advanced spectroscopic techniques to study molecular interactions and drug release. Biophysical studies of interaction of surface groups with membrane proteins and drug-inhibitor interactions will provide background for subsequent analysis of the nanoparticles in their membrane interactions with advance microscopy techniques and examination of the nanoparticle activity in bacterial cells.

Funding notes:

This is funded by BBSRC MIBT https://www.birmingham.ac.uk/research/activity/mibtp

References:

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3. L. S. Watson, J. Hughes, S. T. Rafik, S.T., A. R. Muguruza, P. M. Girio, G. Rochford, G, A. J. MacRobert, N. J. Hodges, E. Yaghini, Z. Pikramenou Nanoscale, 2024, 16, 16500–16509. https://doi.org/10.1039/D4NR01901F

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