Disrupting biofilm formation in nosocomial pathogens

A biofilm by definition is a structured community of bacterial cells enclosed in a self-produced polysaccharide matrix and adherent to an inert or living surface. Bacteria growing in a biofilm are between 10-1,000 times more resistant to antibiotic therapy than their planktonic counterparts. As well as an increased tolerance to antibiotics, the biofilm mode of growth offers protection from various environmental challenges such as the innate and the adaptive immune system as well as offering an increased tolerance to disinfection agents. The annual cost for biofilm infections in the USA is estimated to be $94 billion with more than half a million deaths. Due to the clinical importance of biofilms, there is an urgent need to gain a greater understanding of the regulatory cascades that govern their formation and to identify novel compounds that can inhibit their formation.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen associated with high morbidity and mortality in humans. P. aeruginosa is frequently isolated from patients with Cystic Fibrosis, AIDS and burns patients. In 2018, the World Health Organisation identified carbapenem-resistant P. aeruginosa as number two on the priority pathogen list for which there is an urgent need for the development of novel therapeutic strategies due increasing failure of first line antibiotics. P. aeruginosa is notorious for its ability to form biofilms both within the hospital-built environment and in immunocompromised individuals. Given the link between biofilm formation and poor treatment outcomes, the regulatory networks that control biofilm formation in P. aeruginosa are ideal targets for novel therapeutic intervention strategies.

This proposed research project aims to use high through put screening approaches to identify novel compounds that can disrupt the regulatory networks that control biofilm formation in P. aeruginosa. The mechanism of action of these candidates will then be explored using a range of classical microbiology, ‘omics and genetic approaches. Candidates that demonstrate activity against P. aeruginosa will be tested against other clinically relevant Gram-negative pathogens such as Acinetobacter baumannii. A range of model organisms will be used to determine the efficacy of these compounds in vivo.