Supramolecular Self-Replicating Antimicrobials

Introduction

This project aims to address the urgent need for new antimicrobial agents by developing a conceptually new strategy to damage bacterial membranes with supramolecular fibres.

Mechanism of Action

Dormant (non-assembling) precursors will accumulate in the membrane of bacteria for in situ switch-on of self-assembly and membrane lysis. Specific metabolic routes of bacteria, absent in mammalian cells, will be used to transport supramolecular precursors into the membrane of bacteria with full cell specificity.

Once in the membrane, precursors will combine to generate self-assembling peptide amphiphiles (PAs).

Self-Amplification

Importantly, once formed, the supramolecular assemblies can catalyse their own synthesis in bacterial membranes, causing a dramatic acceleration in PA production and antimicrobial fibrillation. This unprecedented antimicrobial design borrows concepts from:

1. Cooperative self-assembly
2. Supramolecular autocatalysis
3. Rational peptide design

This leads to a self-amplified therapeutic action.

Novelty of the Approach

This will be the first self-replicating antimicrobial that can make copies of itself to boost membrane damage once activated in target pathogens. Co-assembly of PAs and their precursors will create catalytic microenvironments by templation of reactive building blocks.

Project Goals

Overall, this project will lay down structural and mechanistic determinants for biological membrane interfacing with targeted and self-replicating supramolecular nanomaterials.

Broader Implications

In a broader picture, the REPLICATE technology aims to spark a re-conceptualisation of drug design by drawing attention to supramolecular therapeutics, which may open new exciting opportunities in biomedicine not accessible from traditional single-molecule drugs.