Recent figures show that sepsis, the body’s inflammatory response to bacterial infection, is a major killer in the UK. In fact, infections by multidrug-resistant (MDR) bacterial pathogens, represent a major global healthcare burden. This is augmented by the lack of any novel antibiotic development over the last 30 years. In the near future there will be virtually no potent antimicrobials available, making the most routine surgical procedures precarious, high risk practices.

Antimicrobial peptides (AMPs) have emerged as lead candidates for antimicrobial materials. Natively, they are produced by organisms in the plant and animal kingdom, providing the first line of protection against invading pathogens. Whilst there is great diversity in the size (typically 10-100 amino acids), composition and structure, there are obvious trends presented by known AMPs. They are typically amphiphilic and cationic and when a prominent lipid domain is present they are classified as lipopeptide AMPs. The compositional and spatial arrangement of amphiphilic and cationic domains, as well the nature of the lipid component determines AMPs mode of action, with many focused on recognition, interaction and disruption of the bacterial cell envelop. This mode of action, as opposed to the more specific, high affinity, intracellular targeting and mode of action of antibiotics is proposed to delay and/or limit the development of resistance against AMPs. However, there are limitations to the use of AMPs clinically, including high cytotoxicity, discrepancies between in vitro and in vivo testing and high production costs.

Polymer chemistry and macromolecular engineering can provide a cheap, scalable, versatile and modular platform for healthcare, particularly in the fight against antimicrobial resistance (AMR). Not only can it be used to the develop new technologies and therapies to help ‘protect the medicines that protect us’ (WHO’s Urgent health challenges for the next decade), there is also potential for the development of novel macromolecular therapeutics. On one hand, polymers could be used to modulate the efficacy of existing antimicrobial agents e.g. through the development of macromolecular pro-drugs, polymer-drug conjugates or self-assembled drug delivery systems. On the other hand, the discovery and development of living and pseudo-living polymerization methods enables precise synthesis of polymers with excellent compositional and architectural control with broad functional group (monomer) tolerance and scope. Such is the level of control now possible that synthetic polymers are being considered as viable biomimetics for biologics, including bacterial cell envelop targeting antimicrobial peptides (AMPs).

A key challenge associated with the development new antimicrobial agents is understanding their mode of action. The development of high-resolution single molecule and super-resolution microscopy to image the nanoscale organization and dynamics of cell wall synthesis and (re)organization could provide valuable insights and help guide structure/composition/architecture-relationships for modified AMPs and novel antimicrobial polymers that target the bacterial cell envelop.

The specific aims of this project include, to:

1. Develop non-toxic pro-drugs of known AMPs with improved cell membrane interaction (chemistry)
2. Design and synthesise synthetic biomimetics of potent lipopetides with a variety of ratio’s and spatial arrangement of amphiphilic, cationic and lipid domains (chemistry)
3. Evaluate in vitro antimicrobial activity of materials prepared in (1) and (2) (microbiology)
4. In vivo single molecule microscopy and super-resolution microscopy to image the nanoscale interactions and dynamics between the cell envelope and therapeutic candidates (microbiology and advanced imaging)

Techniques