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HEDoctoral network2024–2027

CLEAR · “CLEAR”: Cell Envelope Antibacterials

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2024-01-01 → 2027-12-31
EU contribution
€2,706,538
Participants
15
Scheme
HORIZON-TMA-MSCA-DN

Lines connect the coordinator with its partners.

Results in brief

“CLEAR”: Cell Envelope Antibacterials

Antimicrobial resistance (AMR) has escalated into a global health crisis, with more than one million estimated deaths in 2019 attributable to infections with antibiotic resistant pathogens. Gram-positive bacteria are responsible for a large share of these and among them, the methicillin resistant Staphylococcus aureus (MRSA) is one of the biggest challenges. MRSA strains are resistant to β lactams, which by far are the most widely used class of antibiotic that kill bacteria by inhibiting the synthesis of the bacterial cell wall. Bacteria are surrounded by a cell envelope that is complex and in addition to the cell wall also is composed of a cell membrane and abundant amounts of glycopolymers including the teichoic acids. The hypothesis of the CLEAR training project is that even though resistance has developed to major classes of antibiotics targeting the cell envelope, this compartment of Gram positive bacteria still represents valuable targets for development of new antibacterial therapeutics. CLEAR aims to revitalize the antibiotic development pipeline by advancing three innovative strategies focused on the Gram positive cell envelope. The objective of the first is to inhibit “intrinsic” resistance factors namely bacterial components required for expressing resistance, but not classical resistance genes and thereby potentially restoring β lactam susceptibility. The objective of the second is to identify new drug candidates through pathway directed screening and structural analyses of essential cell wall biosynthesis proteins. The third objective is to explore alternative therapeutic avenues such as exploiting previously unrecognized susceptibility of MRSA to combinations of penicillins and β lactamase inhibitors, by applying bacteriophages or endolysins and by repurposing of approved drugs with the antiplatelet drug ticagrelor as an example. Together, these complementary approaches form the research and training backbone of CLEAR, aiming to generate effective solutions against some of the most challenging Gram positive pathogens driving the AMR crisis.

Data: CORDIS, © European Union

Project objective

The discovery of penicillin initiated the antibiotic era and saved millions from dying of life-threatening bacterial infections such as tuberculosis, sepsis, and pneumonia. Penicillin kills bacteria by inhibiting synthesis of peptidoglycan, an important structure of the bacterial cell envelope. Still today, antibiotics targeting the bacterial cell envelope are the most widely used antibiotics in the world. Unfortunately, resistance to these superior antibiotics is becoming highly prevalent and antibiotic-resistant bacteria represent one of the greatest threats to human health and development today. In the CLEAR (Cell Envelope Anti-bacterials) training network, world-leading researchers from academia have gathered with clinicians and 4 highly relevant SME partners to train a new generation of excellent European scientists in finding novel solutions for targeting the cell envelope of bacteria, who know how findings in academia generate assets to SMEs, and who could bring novel antimicrobial solutions to the market. The proposed research program builds on unique findings of the project partners that allow us to take up innovative and yet feasible approaches 1) to identify novel targets in the cell envelope and to evaluate the lead structure potential of novel agents acting on the cell envelope, 2) to re-sensitize resistant bacteria to existing cell wall antibiotics, 3) and to explore novel therapies acting via the cell envelope. Impacts of this proposal are the re-use of safe and cheap antibiotics, and the drugs already approved for treatment of other diseases as novel antimicrobials. The training program combines a broad range of scientific disciplines such as molecular biology, biochemistry, structural biology, screening technologies, pre-clinical testing with complementary courses in innovation, market potential and business strategies ensuring that the 10 PhDs will be highly competitive for both top European research institutions and the pharma/biotech job market.

Original text from CORDIS.

Participants

  • KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
  • AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MadridSpain
  • CM4CURE SA · LiegeBelgium
  • EBERHARD KARLS UNIVERSITAET TUEBINGEN · TuebingenGermany
  • NAICONS SRL · SaronnoItaly
  • PURAC BIOCHEM BV · GORINCHEMNetherlands
  • RIGAS TEHNISKA UNIVERSITATE · RigaLatvia
  • STATENS SERUM INSTITUT · Kobenhavn SDenmark
  • THE UNIVERSITY OF QUEENSLAND · BrisbaneAustralia
  • UNIVERSIDAD COMPLUTENSE DE MADRID · MadridSpain
  • UNIVERSITE DE LIEGE · LIEGEBelgium
  • UNIVERSITEIT VAN AMSTERDAM · AmsterdamNetherlands
  • UNIVERSITY COLLEGE CORK - NATIONAL UNIVERSITY OF IRELAND, CORK · CorkIreland
  • University of Notre Dame du Lac · Notre DameUnited States
  • Valsts zinatniskais instituts ""Nacionalais petniecibas un inovaciju instituts"""" · RigaLatvia

Links

Data: CORDIS, © European Union