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MycoRailway SIGNED

Discovery and molecular investigation of mycobacterial transporters responsible for iron acquisition

Total Cost €

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EC-Contrib. €

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Partnership

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 MycoRailway project word cloud

Explore the words cloud of the MycoRailway project. It provides you a very rough idea of what is the project "MycoRailway" about.

closely    capture    domain    summary    incognita    siderophore    iron    em    efflux    human    inner    fold    biochemical    membranes    interacting    gain    affinity    structures    building    transporters    thereby    liposomes    import    soluble    offers    sequencing    mediated    bound    engineering    tuberculosis    pathogen    agent    discover    attached    seq    imported    inside    cytoplasm    vulnerable    terra    exporter    little    channels    mycobactin    virulence    devastating    siderocalin    thought    cell    treat    host    receptors    mechanistic    bacteria    loaded    molecular    unusual    mycobacterium    subsequently    protein    mutagenesis    empty    transposon    proton    outer    exported    starve    unknown    release    siderophores    abc    undisputed    acquisition    explore    thoroughly    poorly    despite    infect    carboxymycobactin    carriers    elucidating    mechanism    atomic    deep    binding    therapeutic    crystallography    structural    lab    mycobacterial    humans    proteins    transport    density    cells    strategies    cryo    pathogenic    tn    active    attacking    virtue    critically    exhibiting    point    depends    responsible    insights    ray    unravel    combining    membrane   

Project "MycoRailway" data sheet

The following table provides information about the project.

Coordinator
UNIVERSITAT ZURICH 

Organization address
address: RAMISTRASSE 71
city: ZURICH
postcode: 8006
website: n.a.

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 Coordinator Country Switzerland [CH]
 Total cost 1˙999˙865 €
 EC max contribution 1˙999˙865 € (100%)
 Programme 1. H2020-EU.1.1. (EXCELLENT SCIENCE - European Research Council (ERC))
 Code Call ERC-2017-COG
 Funding Scheme ERC-COG
 Starting year 2018
 Duration (year-month-day) from 2018-04-01   to  2023-03-31

 Partnership

Take a look of project's partnership.

# participants  country  role  EC contrib. [€] 
1    UNIVERSITAT ZURICH CH (ZURICH) coordinator 1˙999˙865.00

Map

 Project objective

To infect humans, the devastating pathogen Mycobacterium tuberculosis critically depends on two closely related siderophores – soluble carboxymycobactin and membrane-bound mycobactin – which capture iron with high affinity inside the host cell. Despite their undisputed importance for virulence, little is known about how these siderophores are exported and imported across the two mycobacterial membranes. Building on my lab’s experience in elucidating transport processes of pathogenic bacteria, we will unravel the molecular mechanism of an unusual ABC exporter which is thought to import iron-loaded siderophores across the inner mycobacterial membrane and to release iron in the cytoplasm by virtue of its attached siderophore interacting domain. Further, we will investigate two proton-driven transporters responsible for the efflux of empty siderophores, exhibiting an unknown protein fold. We will determine atomic structures by combining X-ray crystallography and cryo-EM and thoroughly investigate active in- and efflux of siderophores in liposomes as well as in cells. Siderophore transport across the outer mycobacterial membrane is a terra incognita. By combining high-density transposon mutagenesis with deep sequencing (Tn-Seq), we aim to discover novel receptors, carriers and channels involved in siderophore transport, which are subsequently characterized at the biochemical and structural level. Siderophore-mediated iron acquisition offers a vulnerable attacking point of M. tuberculosis. Using protein engineering, we will develop a human siderocalin exhibiting low affinity binding for carboxymycobactin into a therapeutic agent able to efficiently capture mycobacterial siderophores and thereby starve M. tuberculosis for iron. In summary, we will discover novel proteins involved in iron acquisition, gain mechanistic insights into poorly understood siderophore transport processes at the molecular level and explore novel strategies to treat tuberculosis.

 Publications

year authors and title journal last update
List of publications.
2019 Michael Hohl, Sille Remm, Haig A. Eskandarian, Michael Dal Molin, Fabian M. Arnold, Lea M. Hürlimann, Andri Krügel, Georg E. Fantner, Peter Sander, Markus A. Seeger
Increased drug permeability of a stiffened mycobacterial outer membrane in cells lacking MFS transporter Rv1410 and lipoprotein LprG
published pages: 1263-1282, ISSN: 0950-382X, DOI: 10.1111/mmi.14220
Molecular Microbiology 111/5 2019-12-16
2018 Fabian M. Arnold, Michael Hohl, Sille Remm, Hendrik Koliwer-Brandl, Sophia Adenau, Sasitorn Chusri, Peter Sander, Hubert Hilbi, Markus A. Seeger
A uniform cloning platform for mycobacterial genetics and protein production
published pages: , ISSN: 2045-2322, DOI: 10.1038/s41598-018-27687-5
Scientific Reports 8/1 2019-12-16

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