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

Descrizione del progetto

Verso una nuova strategia antimicrobica: colpire le strutture secondarie di DNA nei batteri

Il DNA G-quadruplex (G4), una struttura secondaria del DNA presente nelle cellule eucariotiche e procariotiche, è stato associato a importanti processi biologici. Nella Pseudomonas aeruginosa, un batterio altamente patogeno responsabile di infezioni ospedaliere, si forma DNA G4 a livello dei promotori genici e la distruzione di queste strutture uccide i batteri. Il progetto G4-AntiBac, finanziato dall’UE, studierà la funzione del DNA G4 nei batteri e svilupperà nuovi composti che prendono di mira queste strutture secondarie come strategia antimicrobica. Il progetto affronta la necessità di identificare nuovi target biomolecolari per lo sviluppo di nuove classi di antibiotici, contribuendo a combattere la resistenza antimicrobica.

Obiettivo

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’.

Parole chiave

Coordinatore

IMPERIAL COLLEGE OF SCIENCE TECHNOLOGY AND MEDICINE
Contribution nette de l'UE
€ 224 933,76
Indirizzo
SOUTH KENSINGTON CAMPUS EXHIBITION ROAD
SW7 2AZ LONDON
Regno Unito

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Regione
London Inner London — West Westminster
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 224 933,76