Breaking the barrier - An integrated multidisciplinary approach to kill Gram-negative bacteria through existing antibiotics by making their outer membrane permeable

Informazioni relative al progetto

BREAKthrough

ID dell’accordo di sovvenzione: 101072632

DOI

10.3030/101072632

Data della firma CE 14 Luglio 2022

Data di avvio 1 Gennaio 2023

Data di completamento 30 Settembre 2027

Finanziato da

• Marie Skłodowska-Curie Actions (MSCA)

Costo totale

Nessun dato

Contributo UE

€ 2 618 488,80

Coordinato da

UNIVERSITE CATHOLIQUE DE LOUVAIN
Belgium

Periodic Reporting for period 1 - BREAKthrough (Breaking the barrier - An integrated multidisciplinary approach to kill Gram-negative bacteria through existing antibiotics by making their outer membrane permeable)

Periodo di rendicontazione: 2023-01-01 al 2024-12-31

Sintesi del contesto e degli obiettivi generali del progetto

Antimicrobial resistance (AMR) represents one of the most urgent public health crises worldwide, severely undermining our ability to treat bacterial infections and leading to significant mortality, morbidity, and economic burden. Gram-negative bacteria pose a particular threat due to their complex outer membrane structure, which severely restricts antibiotic entry and facilitates resistance. The BREAKthrough project addresses this critical challenge by targeting key processes involved in Gram-negative bacterial envelope biogenesis. The overarching objective of BREAKthrough is to identify and exploit novel druggable interactions within these essential bacterial envelope machineries to develop innovative antibacterial compounds capable of permeabilizing the outer membrane. To achieve this, the project integrates multidisciplinary approaches spanning structural biology, chemistry, microbiology, advanced screening technologies, and in vivo infection models. By combining these approaches, BREAKthrough aims to uncover previously unexplored vulnerabilities in Gram-negative bacteria, thereby paving the way for the discovery of novel therapeutic agents; BREAKthrough will significantly enhance our understanding of bacterial envelope biology and antibiotic permeability mechanisms. The development of novel antibacterial compounds will contribute addressing the urgent market need for effective therapies against multidrug-resistant pathogens. Thus, the project is positioned to deliver meaningful solutions in the global fight against antimicrobial resistance.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

During the first reporting period, the BREAKthrough project successfully carried out a range of technical and scientific activities, including the biochemical and structural characterization of major bacterial envelope machineries. Also, significant advances were achieved in elucidating druggable interactions.
Additionally, robust screening methodologies were developed and optimized, including target-based and stress-based assays, as well as innovative in vivo models. These assays facilitated the identification and evaluation of novel synthetic and natural compounds, demonstrating potential to compromise bacterial outer membrane integrity. Chemical synthesis activities led to the generation of novel small-molecule libraries targeting envelope assembly machineries.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The results have strong potential impacts by significantly advancing antibacterial therapies targeting Gram-negative bacterial infections, addressing critical global health challenges related to antimicrobial resistance. To ensure further uptake and success, additional research, preclinical validation, comprehensive IP strategies, and supportive regulatory frameworks will be crucial.

The BREAKthrough DCs at the second annual meeting in Bled, Slowenia