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

Project Information

BREAKthrough

Grant agreement ID: 101072632

DOI

10.3030/101072632

EC signature date 14 July 2022

Start date 1 January 2023

End date 30 September 2027

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 2 618 488,80

Coordinated by

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)

Reporting period: 2023-01-01 to 2024-12-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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