Aerogel based delivery of furanones for the inhibition of quorum sensing and biofilm formation in the wound pathogen Pseudomonas aeruginosa

Abstract

A chronic wound is any wound that does not progress through the normal stages of healing. These wounds can take months or even years to resolve and, in many cases, will never fully heal. Chronic wounds are highly prevalent, with up to 3% of people over 60 and as many as 5% of people over 80 suffering from a chronic wound. Patients with chronic wounds often suffer from chronic pain, limited mobility, social isolation, and poorer mental health. Not only are these wounds highly traumatic for patients, but they are also a significant burden for the NHS, with their treatment costing approximately £5.3 billion per annum.
​​​​​​​There are several reasons why a wound might fail to heal. The most common cause, however, is bacterial infection, and one of the most common causative organisms is Pseudomonas aeruginosa. When present in a wound, P. aeruginosa grows primarily in the form of a biofilm, a collection of bacterial cells encased in a self-produced polymer matrix. This matrix makes the bacteria highly resistant to antibiotic treatment, making wound infections very difficult, and often impossible, to eradicate.
The formation of bacterial biofilms is governed by a process known as quorum sensing, in which bacteria produce and detect small signalling molecules known as autoinducers. This form of communication allows the cells to coordinate complex, population-wide, behaviours such as virulence factor expression, and biofilm formation.
Several methods of disrupting quorum sensing, for example, via enzymatic degradation of the signalling molecules, have been proposed. One method competitive inhibition wherein a compound which competitively binds to the bacterial quorum sensing signalling receptors, effectively blocks the cell’s ability to take part in quorum sensing. Many synthetic and natural compounds have been shown to be capable of such competitive inhibition but perhaps the most well studied of these are furanones.
Furanones are one such family of naturally occurring chemicals which are structurally similar to the signalling molecules used by P. aeruginosa. This allows furanones to competitively bind to the quorum sensing signal receptor, thus, minimising biofilm formation by P. aeruginosa populations.
This thesis aimed to develop a novel method of delivering furanones to chronically infected wounds. This work demonstrated that, due to their inherent instability, a minimally crosslinked polymer aerogel was the most appropriate system for the controlled delivery of these compounds. Further, this thesis has demonstrated that, whether they are applied early in the biofilm formation process or to mature biofilms, two furanones, 4-hydroxy-2,5-dimethyl-3(2H) furanone (HDMF) and sotolon, are capable of significantly reducing biofilm biomass in vitro. The final experimental chapter of this thesis aimed to develop a novel, clinically representative, in vitro model of chronic wound biofilm that could be used to assess furanone loaded aerogels as potential antibiofilm wound therapeutics. The developed model was validated by showing efficacy of clinically relevant wound dressings and, subsequently, was used to demonstrate that sotolon-loaded aerogels showed great potential for reducing biofilm in chronic wounds.
This thesis concludes that, though complex to include in pharmaceutical formulations, naturally occurring furanones have excellent potential to be used as antibiofilm wound therapeutics. Furthermore, when incorporated into a minimally crosslinked poly (vinyl alcohol) aerogel material, these compounds retain their activity and can be delivered to clinically representative biofilms where they reduce biofilm biomass.

Date of Award	Feb 2021
Original language	English
Supervisor	Nigel Ternan (Supervisor) & Paul Mc Carron (Supervisor)