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

Descripción del proyecto

Hacia una nueva estrategia antimicrobiana: actuar sobre las estructuras secundarias de ADN de las bacterias

El ADN G-quadruplex (G4), una estructura secundaria de ADN que se encuentra en las células eucariotas y procariotas, se ha asociado con procesos biológicos importantes. En «Pseudomonas aeruginosa», una bacteria muy patógena responsable de infecciones nosocomiales, el ADN G4 se forma en los promotores genéticos y la ruptura de estas estructuras mata las bacterias. El proyecto financiado con fondos europeos G4-AntiBac investigará la función del ADN G4 en las bacterias y desarrollará nuevos compuestos dirigidos contra estas estructuras secundarias como estrategia antimicrobiana. El proyecto aborda la necesidad de identificar nuevas dianas biomoleculares para el desarrollo de nuevas clases de antibióticos que ayuden a luchar contra la resistencia antimicrobiana.

Objetivo

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’.

Palabras clave

Coordinador

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Aportación neta de la UEn
€ 224 933,76
Dirección
SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
SW7 2AZ LONDON
Reino Unido

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Región
London Inner London — West Westminster
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 224 933,76