Objective
This project will study substrate translocation mechanisms of multi-component drug-efflux pumps that transport molecules across membranes in Gram-negative bacteria. These pumps serve both protective and virulence associated functions, by forming channels associated with the export of invasive proteins and the efflux of toxic compounds. At the same time, the outer membrane component of the pump, TolC, is a point of weakness for the bacterium since it is a receptor for bacteriophages and is a point of entry f or certain bactericidal proteins, known as colicins.
The initial stages of the project will involve model building and refining of the crystal structure of a complex composed of TolC and a truncated form of the colicin E1. In parallel, crystallisation of t he complex between TolC and full-length colicin E1 protein will be pursued. These structures are expected to provide information on the protein translocation mechanisms.
In a second aspect of the project, mutants will be engineered that trap and stabilize active transport assemblies from pathogenic species. We will use the available structural information to design covalent assemblies involving TolC-related proteins with other components of the transport machinery, including the AcrA family of membrane fusion proteins. One tool that we will develop in this study is a novel lipopeptide compound that will be implemented for solubilization of membrane protein complexes. These compounds will be tested for suitability for crystallisation of individual pump components as well as for mass-spectrometric analyses of the complete drug efflux pumps. These studies will give clues to the still enigmatic role of the fusion proteins in the formation of the drug efflux channels. Apart from fundamental knowledge, the results from this project may have practical implications, since multi-drug resistance pumps are promising drug targets and are responsible for the inactivity of increasing number of antimicrobial agents.
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.
- engineering and technology materials engineering crystals
- natural sciences biological sciences microbiology bacteriology
- natural sciences biological sciences biochemistry biomolecules proteins
- medical and health sciences basic medicine pharmacology and pharmacy drug resistance multidrug resistance
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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.
Topic(s)
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.
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.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2002-MOBILITY-5
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Funding Scheme
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.
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.
Coordinator
CAMBRIDGE
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.