2-Alkyl-4-quinolone signalling in Pseudomonas and Burkholderia

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Pseudomonas and Burkholderia are two related groups of Gram-negative bacteria which are commonly found in water, soil and on the surfaces of plants and animals. Some species are pathogenic for human and plants, some cause food and industrial spoilage problems while others are beneficial and promote plant growth and can be used for biodegradation of hydrocarbons and plastics. This project will focus mainly on Pseudomonas aeruginosa, a human pathogen which is a common cause of infections in hospital patients and a major problem in individuals with cystic fibrosis. P. aeruginosa produces an armoury of virulence factors and is resistant to many conventional antibiotics and so infections with this organism can be difficult to treat and it is almost impossible to eradicate from the lungs of cystic fibrosis patients. Bacteria such as P. aeruginosa use small chemical signal molecules to co-ordinate the activities of the individual cells within the bacterial population. This bacterial cell-to-cell communication device is called quorum sensing (QS). P. aeruginosa uses at least two chemically distinct classes of QS signal molecules, the N-acylhomoserine lactones (AHLs) and the 2-alkyl-4-quinolones (AQs) to control production of virulence factors which enable the organism to combat the immune system and cause tissue damage and disease. Inactivation of QS by mutating the genes responsible for the production and action of the AQ (and AHL) signal molecules renders the organism incapable of causing infections. QS systems are therefore potential targets for new antibacterial agents. Understanding how AQ-signalling works at a molecular level will allow us to develop new strategies for controlling pathogenic bacteria such as P. aeruginosa. In this project we propose to build on our previous work to understand in more detail how P. aeruginosa synthesizes AQ signal molecules, how AQs control virulence factor production, how AQ-signalling is affected by a lack of oxygen and to discover the role of AQs in scavenging for iron (an essential bacterial nutrient) and in stimulating the death of a proportion of the bacterial population under stressful conditions for the benefit of the bacterial population as a whole. We also plan to extend these studies to two Burkholderia species, Burkholderia plantarii and Burkholderia glumae which can cause infections in humans but which are primarily pathogens of rice. From our understanding of the molecular basis of AQ-signalling, we will also explore the potential of AQ-degrading enzymes for controlling Pseudomonas and Burkholderia infections and synthesize a series of analogues of AQs and AQ-precursors which will be screened as possible new antibacterial agents. Thus this research will be of benefit by providing useful scientific tools, by contributing to the understanding of fundamental biological systems and by designing and screening novel antibacterial agents for the prevention and treatment of Pseudomonas and Burkholderia infections