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HEDoctoral network2023–2027

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

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-01-01 → 2027-09-30
EU contribution
€2,618,489
Participants
19
Scheme
HORIZON-TMA-MSCA-DN

Lines connect the coordinator with its partners. CORDIS does not always give exact coordinates for projects before 2014. These points are placed at city or country level.

Results in brief

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

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.

Data: CORDIS, © European Union

Project objective

Antimicrobial resistance, which is caused by multi-drug-resistant bacterial pathogens is a global health emergency. Gram-negative bacteria (GNB) notably hinder effective treatment because of their impermeable outer membrane (OM). Consequently, many standard-of-care (SOC) antibiotics cannot access intracellular targets in GNB. The objective of the BREAKthrough European Training Network (ETN) is to sensitise GNB to these antibiotics by making their OM permeable. To this end, we will develop inhibitors of three protein machineries that are responsible for OM maintenance. Importantly, many known antibacterial agents have characteristics different from drugs that are directed against targets in mammalian cells. To define better rules for antibacterial drug development a data hub will be created to assemble information on the physico-chemical characteristics of molecules that can pass the OM.To achieve these goals, a multi-disciplinary academic-industrial consortium has been assembled with organic chemists, computational chemists and specialists in high-throughput drug screening, zebrafish infection models, bacterial morphogenesis and the molecular biology of the three targets. The expected outcomes of the BREAKthrough ETN include (i) the development of new chemical space rules for drugs that need to cross the OM, (ii) the discovery of new inhibitors that interfere with OM maintenance to overcome the insensitivity of Gram-negative pathogenic bacteria towards SOC antibiotics and (iii) providing 10 Early Stage Researchers with scientific, technical, business and transferable skills to become professional drug developers with a keen eye for the hurdles in the development of these drugs in an industrial context.

Original text from CORDIS.

Participants

  • UNIVERSITE CATHOLIQUE DE LOUVAIN · LOUVAIN LA NEUVECoordinatorBelgium
  • ABAC THERAPEUTICS, SL · Esplugues De LlobregatCity levelSpain
  • ACCELOPMENT SCHWEIZ AG · ZurichSwitzerland
  • AICURIS ANTI-INFECTIVE CURES AG · WUPPERTALGermany
  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisFrance
  • F. HOFFMANN-LA ROCHE AG · BaselSwitzerland
  • FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA · TARRAGONASpain
  • FUNDACION PRIVADA INSTITUTO DE SALUD GLOBAL BARCELONA · BarcelonaSpain
  • NAICONS SRL · SaronnoItaly
  • STICHTING AMSTERDAM UMC · AmsterdamNetherlands
  • STICHTING VU · AmsterdamNetherlands
  • SYMERES NETHERLANDS BV · NijmegenNetherlands
  • Syngulon · SeraingBelgium
  • THE UNIVERSITY OF QUEENSLAND · BrisbaneAustralia
  • UNIVERSITA DEGLI STUDI DI MILANO · MilanoItaly
  • UNIVERSITAT DE BARCELONA · BarcelonaSpain
  • UNIVERSITAT ROVIRA I VIRGILI · TarragonaSpain
  • UNIVERSITY OF NEWCASTLE UPON TYNE · Newcastle Upon TyneUnited Kingdom
  • UNIVERZA V LJUBLJANI · LjubljanaSlovenia

Links

Data: CORDIS, © European Union