Microorganisms use quorum sensing (QS), a cell density dependent process, to communicate. This QS mode of interchange leads to the production of a variety of virulence factors, coordination of complex bacterial behaviours, such as swarming motility, degradation of host tissue and biofilm formation. QS is implicated in numerous human infections and, consequently, researchers have sought ways of effectively inhibiting the process in pathogenic bacteria. Two decades ago, furanones were the first class of chemical compounds identified as Pseudomonas aeruginosa QS inhibitors (QSIs). P. aeruginosa is a ubiquitous organism, capable of causing a wide range of infections in humans, including eye and ear infections, wound infections and potentially fatal bacteraemia and thus novel treatments against this organism are greatly needed. This review provides a brief background on QS and the use of furanones as QSIs. Based on the effectiveness of action, both in vivo and in vitro, we will explore the use of furanones as potential antimicrobial therapeutics and conclude with open questions.

Antimicrobial resistance is one of the most pressing concerns of our time. The human diet is rich with compounds that alter bacterial gut communities and virulence-associated behaviours, suggesting food additives may be a niche for the discovery of novel anti-virulence compounds. Here, we identify three artificial sweeteners, saccharin, cyclamate and acesulfame-K (ace-K), that have a major growth inhibitory effect on priority pathogens. We further characterise the impact of ace-K on multidrug-resistant Acinetobacter baumannii, demonstrating that it can disable virulence behaviours such as biofilm formation, motility and the ability to acquire exogenous antibiotic-resistant genes. Further analysis revealed the mechanism of growth inhibition is through bulgemediated cell lysis and that cells can be rescued by cation supplementation. Antibiotic sensitivity assays demonstrated that at sublethal concentrations, ace-K can resensitise A. baumannii to last resort antibiotics, including carbapenems. Using a novel ex vivo porcine skin wound model, we show that ace-K antimicrobial activity is maintained in the wound microenvironment. Our findings demonstrate the influence of artificial sweeteners on pathogen behaviour and uncover their therapeutic potential.

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Chronic wounds are a significant issue in healthcare, presenting a considerable economic burden to the NHS and a serious health risk to patients. The majority of non-healing wounds have been shown to contain a biofilm which prolongs the inflammatory stage of wound healing and significantly delays wound healing. This often causes a normal wound to progress and become chronic, presenting further problems for patients including increased risk of secondary infection, further deterioration of the wound and an increase in treatment intensity. This project aims to assess the efficacy of several compounds in modulating the formation of biofilms in a number of clinically relevant pathogens when used at sub-inhibitory concentrations. The organisms used in this project include Pseudomonas aeruginosa and Staphylococcus aureus. We aim to test the efficacy of three plant derived compounds including 4-hydroxy-2,5-dimethyl-3(2 h) furanone (HDMF), 2-methyltetrahydrofuran-3-one (MTHF) and l-ascorbic acid. Future work will characterise the efficacy of these compounds when delivered to a biofilm from a hydrogel based delivery system. At sub-inhibitory concentrations in pure solution, candidate molecules tested to date showed no ability to reduce biofilm formation. Indeed, treatment with HDMF resulted in greater production of biofilm in P. aeruginosa and treatment with all compounds showed no difference in biofilm formation by S. aureus. To characterise the impact of hydrogel based delivery on compound efficacy all candidate molecules were loaded into a hydrogel and shown to be effectively released from it. Experiments to characterise the modulatory potential of these compounds when released from a hydrogel are currently underway.