Polyvalent Multifunctional Nanoparticles to Address Resistance Bacteria

Summary

The emergence of antibiotic resistant bacteria, e.g. methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE) has created a major global health problem, affecting millions of patients worldwide.[1] For example, vancomycin (Van) is a potent antibiotic for treating Gram-positive bacterial infection. Van specifically binds to bacteria cell wall mucopeptide terminal D-Ala-D-Ala residues by forming five H-bonds which sterically prevents cell-wall cross-linking and inhibit microbial growth. Mutation of a single amino acid residue from D-Ala-D-Ala to D-Ala-D-Lac in VRE deletes a single H-bond, reducing its Van binding affinity by ~1000 fold and rendering Van therapeutically useless.[2] By linking two Vans together, Van dimers have shown enhanced potency against VRE,[3] although its potency still need to be further improved to meet the clinical need.

This project aims to develop a polyvalent multifunctional nanoparticle (PMN) strategy to address the bacterial antibiotic resistance problem. Using Van as a model antibiotic, we will create multivalent display of Van on the nanoparticle surface which can bind simultaneously to multiple D-Ala-D-Lac residues on the VRE surface, greatly enhance its binding affinity and overcome VREs resistance mechanism. Meanwhile, the unique chemico-/physical properties (e.g. photothermal for nanorod)[4] and intrinsic anti-bacterial property of nanoparticles (e.g. silver)[5] will be further combined to offer potent multi-modal anti-bacterial action.

A major limitation of current antibacterial nanomaterial research has been too focused on pursuing antibacterial potency only without or little consideration of their stability and interactions with biological media and renal clearance. These are key requiremens for real world application and clinical approval. As a result, most current antibacterial nanomaterials have little proposet of being translated into useful drugs despite high antibacterial potency in vitro. Here we will address this problem by balancing these needs at the begining of our antibacterial nanomaterials design, greatly enhancing their chances for clinical impact.

Specifically, this project will,

1) synthesise and characterise lipoic acid-PEG or zwitterionic based multi-functional ligands to enhance nanoparticle stability and reduce non-specific interactions with serum proteins and other biological compotents;

2) synthesise and characterise nanoparticles of different sizes to allow for renal clearance;

3) investigate how particle size, shape and surface chemistry determine its anti-bacterial potency;

4) prepare polyvalent Van-nanoparticles and evaluate the valency, shape and size-dependence on anti-bacterial potency;

5) investigate the potency of combined multimodal treatment against resistant bacteria (e.g. VRE, with Prof. Alex O’Neil, FBS).

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