Infectious diseases remain a leading cause of death worldwide and a developing resistance to antimicrobial drugs is a significant threat to humans. The World Health Organization has identified antimicrobial resistance as one of the most important problems that affects human health. Pseudomonas aeruginosa, is a dreadful Gram-negative bacterium pathogen associated with severe acute and chronic human diseases. The emergence of a number of Gram-negative pathogens, including a number of strains of P. aeruginosa, that are resistant to the front-line antibiotic therapies is a global concern – accounting 10 – 15 % of nosocomial (hospital-acquired) infections world-wide, and the pipeline of antibiotics is essentially empty. P. aeruginosa has been ranked by WHO in the top three of organisms that are critical and needing immediate attention. Therefore, it is urgent to identify and validate alterative biomolecular targets to develop new antibacterial agents capable of either killing these multi-drug resistant (MDR) bacteria or make them susceptible again against current antibiotics. Recently, bioinformatic studies have shown that G-quadruplex DNA (G4 DNA) sequences are prevalent in bacteria, particularly in gene promoter regions of pathogenic bacteria. Furthermore, a number of recent studies have demonstrated that quadruplexes do indeed play a role in virulence of Gram-negative bacteria such as E. coli. Therefore, G4 DNA structures are potentially interesting new targets for the development of antibacterial drugs. The proposed project was aimed at developing a new approach to tackle antimicrobial resistance through targeting G4 DNA structures of relevance to bacteria. To achieve this, following scientific objectives have been proposed.
1. Develop small molecules to target G4 DNA structures of relevance to P. aeruginosa.
2. Fully characterise the interaction of a library of compounds against the three G4 structures (i.e. from murE, ftsB and MexC) and study their selectivity over other DNA topologies
3. Establish the activity and uptake profile of new G4 DNA binders against P.aeruginosa strains.
4. Determine the ability of new molecules to modulate the expression of murE, ftsB and MexC genes.
