Objective
Overcoming the barriers that the cell envelope and efflux pumps provide to Gram-negative bacteria is a major bottleneck in the discovery and development of new antibiotics. To respond to this Call we are extending our current network on antibiotic translocation and propose an ambitious project ranging from identification of novel resistance mechanisms in clinical bacterial isolates to crystallization of molecular resistance components and all-atom modeling to determine the kinetics of permeation. Our particular strength lies in the identification and quantification of transport proteins involved in membrane permeation at the cellular level combined with our expertise in quantifying the rate limiting steps of translocation at atomic level. Based on our experience we intend to:
1. develop multiple assays to determine intracellular concentrations of small molecules
2. increase the overall structural knowledge of outer membrane proteins
3. extend knowledge on active-uptake transport systems, such as iron transport
4. identify novel targets whose modulation can alter the penetration of other small molecules
5. obtain as complete a picture as possible of small molecule penetration into and efflux out of bacterial cells
Combining the research question at different levels we expect to understand the complexity of membrane permeability. In particular, we are convinced that our molecular approach is able to provide a general template for a guided design of antibiotics to achieve high permeability.
In addition, we will create a data base to allow the sharing of antibacterial R&D information on an unprecedented level. Also, via careful analysis of this information we intend to provide learnings as best practices that will lead to an increase in the overall efficiency of antibacterial R&D.
Fields of science
Call for proposal
IMI-JU-06-2012
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Coordinator
TW89GS Brentford
United Kingdom
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Participants (27)
28725 Bremen
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09124 Cagliari
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KY16 9AJ St Andrews
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60323 Frankfurt Am Main
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4 Dublin
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80339 Munchen
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28359 BREMEN
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08036 Barcelona
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49084 OSNABRUCK
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NE1 7RU Newcastle Upon Tyne
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79106 Freiburg
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1211 Geneve
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4051 Basel
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Participation ended
22525 Hamburg
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Participation ended
48149 Münster
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91190 Saint Aubin
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75012 Paris
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13820 Ensues La Redonne
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13284 Marseille
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94250 GENTILLY
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151 85 Sodertaelje
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4058 BASEL
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2340 Beerse
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75794 Paris
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3511 MJ Utrecht
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2500 Valby
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80686 Munchen
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