Project description
Reactivating antibiotics against multidrug-resistant infections
Multidrug-resistant (MDR) bacterial infections threaten modern medicine due to limited antibiotic development. Research reveals that functional membrane microdomains (FMMs) in prokaryotes play a crucial role in protein folding without ATP. Disrupting these FMMs collapses the bacterial proteome, reduces infection severity, and resensitises MDR pathogens to antibiotics. The ERC-funded CLAMP project will characterise the role of FMMs in bacterial proteostasis and develop anti-FMM drugs to reactivate antibiotics against MDR infections, thereby deepening our understanding of cellular membrane organisation. The project will describe the molecular organisation of FMMs and their role in preventing protein misfolding, investigate proteome stabilisation mechanisms independent of ATP and their significance in pathogenesis, and develop anti-FMM drugs to tackle MDR infections and restore sensitivity to traditional antibiotics.
Objective
Multi-drug resistant (MDR) bacterial infections threaten all the advances in modern medicine after the industry nearly abandoned antibiotic development and no mechanism to suppress antibiotic resistance has been found. However, our results indicate that this mechanism does exist and is conserved in functional membrane microdomains (FMM) in all prokaryotes. We discovered bacterial FMM, akin to eukaryotic lipid rafts, and demonstrated their crucial role in preserving proteins correctly folded at no ATP cost. FMM are essential for pathogens survival during infections thus, FMM perturbation causes the bacterial proteome to collapse, particularly affecting heterologous proteins responsible for MDR. This leads to attenuated infections and additionally re-sensitizing MDR pathogens to antibiotics. Studying FMM will transform our understanding of cellular membrane organization and its connection to protein misfolding disorders. Accordingly, this proposal will undertake an ambitious molecular characterization of FMM and its impact on bacterial proteostasis, and we will apply this knowledge to bring closer to the clinic a battery of anti-FMM drugs that target FMM to reactivate antibiotics against MDR infections. To achieve this, a first structural goal will describe FMM molecular organization, how FMM operate to prevent protein misfolding, and the molecular principles driving the assembly of membrane microdomains in cells. Secondly, a functional goal will describe the mechanism of proteome stabilization independent of ATP and its crucial role in pathogenesis. Finally, an applied goal will be to implement anti-FMM drugs to eliminate MDR infections and re-sensitize them to conventional antibiotics. This proposal unveils a new frontier in understanding the cellular programs for membrane compartmentalization, their connection to protein-misfolding cellular dysfunction, and the possibility of applying this knowledge to revitalize classical antibiotics against MDR infections.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2024-ADG
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
28006 MADRID
Spain
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