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

Description du projet

Vers une nouvelle stratégie antimicrobienne: le ciblage des structures secondaires d’ADN dans les bactéries

L’ADN G-quadruplexe (G4), une structure secondaire de l’ADN observable au sein des cellules eucaryotes et procaryotes, a été associé à des processus biologiques importants. Chez Pseudomonas aeruginosa, une bactérie hautement pathogène responsable d’infections nosocomiales, l’ADN G4 se forme au niveau des promoteurs des gènes, et la perturbation de ces structures tue les bactéries. Le projet G4-AntiBac, financé par l’UE, étudiera la fonction de l’ADN G4 au sein des bactéries et développera de nouveaux composés pour cibler ces structures secondaires dans le cadre d’une stratégie antimicrobienne. Le projet répond à la nécessité d’identifier de nouvelles cibles biomoléculaires pour le développement de nouvelles classes d’antibiotiques, visant à combattre la résistance aux antimicrobiens.

Objectif

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’.

Mots‑clés

Coordinateur

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Contribution nette de l'UE
€ 224 933,76
Adresse
SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
SW7 2AZ LONDON
Royaume-Uni

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Région
London Inner London — West Westminster
Type d’activité
Higher or Secondary Education Establishments
Liens
Coût total
€ 224 933,76