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Sensoring for new antibiotics with the bd oxidase from pathogenic bacteria
Funder: French National Research Agency (ANR)Project code: ANR-19-MRS1-0010
Funder Contribution: 30,000 EUR

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Description

It is obvious that the current portfolio of antimicrobial agents and clinical diagnostics will not provide sufficient protection of humans over the long term. This project addresses today’s urgent need for new cellular targets, which will hopefully lead to new antimicrobial drugs that act with novel molecular and cellular mechanisms. Our ambition is to validate cytochrome bd oxidases, a family of multi-subunit membrane proteins, as privileged targets for future antibacterial drugs. Cytochrome bd oxidases, are solely present in bacteria, including several pathogens such as Escherichia coli responsible for several food-induced diseases in Europe, Mycobacterium tuberculosis, which causes the deadliest sickness in Human history and Klebsiella pneumonia often involved in nosocomial infections. The bd oxidases are part of the respiratory chain within these bacteria, however, they are believed to play a crucial role in the protection against oxidative stress, in their virulence, adaptability and antibiotics resistance. No homologues are found in eukaryotes. A comprehensive understanding of the structure, assembly and catalytic mechanism of bd oxidase requires knowledge of their unique structure, the specific reaction mechanism, the interaction with the membrane and possibly the knowledge of chaperones involved in their assembly. Such information is only gained through the integration and combination of a broad range of state-of-the-art analytical techniques. Screening techniques will be set up for medium-to-high throughput methods to search compound libraries for their ability to inhibit the bd oxidase from pathogenic bacteria possibly leading to the development of new antibiotics. The required technical know-how by far exceeds the possibilities of a single research group and international scientific cooperation is imperative. The researchers in this consortium from six countries are working on different aspects of this broad, topical and most important research area, such as the integration of proteins into biological membranes, the structure of membrane proteins, the assembly of multi-subunit complexes in the membrane, the insertion of cofactors, the binding of the substrates, coupling of the redox reaction with charge translocation and with the interactions between the membrane and the embedded bd oxidase. At least two industrial partners have been identified that will support the development of the screening techniques. Establishing and institutionalizing such cooperation within the framework of EU-ITN will not only create a strong research consortium, it will also generate a platform for students to acquire a broad spectrum of skills that will give them a head start on the competitive job market for young scientists.

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