G4-AntiBac · Targeting G-quadruplex DNA Structures in Bacteria to Combat Antimicrobial Resistance
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-04-06 → 2023-04-05
- EU contribution
- €224,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Targeting G-quadruplex DNA Structures in Bacteria to Combat Antimicrobial Resistance
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.
Data: CORDIS, © European Union
Project 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’.
Original text from CORDIS.
Participants
- IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union