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CORDIS

Targeting G-quadruplex DNA Structures in Bacteria to Combat Antimicrobial Resistance

Project description

Towards a new antimicrobial strategy: targeting secondary DNA structures in bacteria

The G-quadruplex (G4) DNA, a secondary structure of DNA seen in both eukaryotic and prokaryotic cells, has been associated with important biological processes. In Pseudomonas aeruginosa, a highly pathogenic bacterium responsible for hospital-acquired infections, G4 DNA forms at the gene promoters, and disruption of these structures kills bacteria. The EU-funded G4-AntiBac project will investigate the function of G4 DNA in bacteria and develop novel compounds that target these secondary structures as an antimicrobial strategy. The project addresses the need for the identification of novel bio-molecular targets for the development of new classes of antibiotics, helping to combat antimicrobial resistance.

Objective

There is a pressing need to develop new antimicrobial approaches to combat bacterial resistance to antibiotics. Pseudomonas aeruginosa – a dreadful Gram-negative bacterium pathogen associated with severe acute and chronic human diseases – is responsible for 10-15 % of hospital-acquired infections worldwide. Thus, it is important to identify new biomolecular targets in bacteria and design new molecules that can selectively target them. This project aims to study G-quadruplex DNA (G4 DNA) structures as a new bio-molecular target for the development of new classes of antibiotics. G4 DNA is a non-canonical structure of DNA whose formation has been associated to a number of important biological processes. While the function of G4 DNA is well established in eukaryotic cells, far less is known about their functions in bacteria. Preliminary data from the host group has shown that G4 DNA’s can form in gene promoter regions of the genome in P. aeruginosa. They have also shown that metal complexes can bind to this G4 DNA regions and display antibacterial activity. In this project, I propose to develop novel compounds (via a ‘target-guided synthesis’ approach) that can specifically bind with high affinity to G4 DNA structures of relevance to bacteria. If the newly developed bacterial G4 DNA binders exhibit low cellular uptake, I propose to implement the well-established liposomal delivery strategies to improve their uptake into the targeted bacterial strains. Finally, the highly active compounds will be used to study the proposed gene regulatory role that G-quadruplexes play in P. aeruginosa. My proposed research falls under one of the key priorities (i.e. Infectious diseases and improving global health) of the Horizon-2020 work programme. The outcome of the proposed study will have impact in addressing one of the key objectives (i.e. Develop New Therapeutics and Alternatives) of the recently documented ‘European One Health Action Plan against Antimicrobial Resistance’.

Keywords

Coordinator

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Net EU contribution
€ 224 933,76
Address
SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
SW7 2AZ LONDON
United Kingdom

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Region
London Inner London — West Westminster
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 224 933,76