Antibiotic resistance is a global threat to human health. This project is focused on Pseudomonas aeruginosa a major cause of hospital acquired infections such as ventilator associated pneumonia (VAP), bacteremia and catheter-associated urinary tract infections. In addition, chronic lung infection with P. aeruginosa is the leading cause of mortality in patients with cystic fibrosis. A major and rapidly growing problem in treating P. aeruginosa infection is antibiotic resistance. Clinical isolates of P. aeruginosa with resistance to nearly all available antibiotics are prevalent worldwide and between 18 and 25% of clinical isolates are multidrug resistant, showing resistance to three or more frontline antibiotics. In addition, the ability of P. aeruginosa to form multi-drug resistant biofilms during chronic infection and the appearance of antibiotic resistant phenotypic variants during prolonged antibiotic therapy can render this pathogen essentially untreatable with existing therapeutic options. Consequently, there is an urgent requirement to develop new antibiotics for the treatment of P. aeruginosa infections.
An alternative strategy for antibiotic discovery is to utilize the narrow spectrum antibiotics used by bacteria for intraspecies competition. In Gram-negative bacteria such as P. aeruginosa, Escherichia coli and Klebsiella pneumoniae these take the form of related high molecular weight protein antibiotics (bacteriocins), termed pyocins, colicins and klebicins, respectively. The use of bacteriocins will, in contrast to the use of broad-spectrum antibiotics, allow specific pathogens to be targeted leaving the wider microbial community intact. The devastating impact of conventional antibiotics on the structure, composition and functionality of human microbiomes is now recognised with increased antibiotic use in early life associated with an increased risk of developing chronic inflammatory diseases such as IBD and asthma in later life. Consequently, there is a growing consensus that the next generation of antibiotics should be precision narrow-spectrum therapeutics, able to target specific pathogenic bacteria without collateral damage to the wider microbiota.
We have identified and produced a range of bacteriocins active against P. aeruginosa and have demonstrated efficacy for a number of these including the lectin-like bacteriocin pyocin L1. However, for the lectin-like pyocins we lack understanding of the mechanism of killing, which limits our ability to engineer and further develop these potent antibiotics as potential therapeutics. This is in part due to the mysterious evolutionary origins of the lectin-like bacteriocins, which are distinct among the protein bacteriocins and possess domains that appear to closely resemble plant-lectins. In addition, we have little information on the activity of these protein antibiotics against clinically important bacterial biofilms and their synergistic activity with antibiotics currently used to treat P. aeruginosa infection.
Aims
In this project, we will utilize a multidisciplinary approach, including biochemical, biophysical, genomic and bioinformatic analysis to investigate the mechanism of killing of the lectin-like bacteriocins. Our specific aims are:
1. Identify the molecular target in P. aeruginosa through which the lectin-like bacteriocins exert their killing activity
2. Determine the activity of pyocin L1 against biofilms of diverse P. aeruginosa isolates and investigate synergy with currently used antipseudomonal antibiotics.
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