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dc.contributor.author
Hartkoorn, Ruben C.
dc.contributor.author
Sala, Claudia
dc.contributor.author
Neres, João
dc.contributor.author
Pojer, Florence
dc.contributor.author
Magnet, Sophie
dc.contributor.author
Mukherjee, Raju
dc.contributor.author
Uplekar, Swapna
dc.contributor.author
Boy-Röttger, Stefanie
dc.contributor.author
Altmann, Karl-Heinz
dc.contributor.author
Cole, Stewart T.
dc.date.accessioned
2019-08-20T13:32:14Z
dc.date.available
2017-06-10T09:51:52Z
dc.date.available
2019-08-20T13:32:14Z
dc.date.issued
2012-10-01
dc.identifier.issn
1757-4676
dc.identifier.issn
1757-4684
dc.identifier.other
10.1002/emmm.201201689
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/56749
dc.identifier.doi
10.3929/ethz-b-000056749
dc.description.abstract
Tuberculosis, a global threat to public health, is becoming untreatable due to widespread drug resistance to frontline drugs such as the InhA‐inhibitor isoniazid. Historically, by inhibiting highly vulnerable targets, natural products have been an important source of antibiotics including potent anti‐tuberculosis agents. Here, we describe pyridomycin, a compound produced by Dactylosporangium fulvum with specific cidal activity against mycobacteria. By selecting pyridomycin‐resistant mutants of Mycobacterium tuberculosis, whole‐genome sequencing and genetic validation, we identified the NADH‐dependent enoyl‐ (Acyl‐Carrier‐Protein) reductase InhA as the principal target and demonstrate that pyridomycin inhibits mycolic acid synthesis in M. tuberculosis. Furthermore, biochemical and structural studies show that pyridomycin inhibits InhA directly as a competitive inhibitor of the NADH‐binding site, thereby identifying a new, druggable pocket in InhA. Importantly, the most frequently encountered isoniazid‐resistant clinical isolates remain fully susceptible to pyridomycin, thus opening new avenues for drug development.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Wiley
en_US
dc.rights.uri
http://creativecommons.org/licenses/by-nc/3.0/
dc.subject
Drug discovery
en_US
dc.subject
InhA
en_US
dc.subject
Isoniazid
en_US
dc.subject
Pyridomycin
en_US
dc.subject
Tuberculosis
en_US
dc.title
Towards a new tuberculosis drug: pyridomycin – nature's isoniazid
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution-NonCommercial 3.0 Unported
dc.date.published
2012-09-17
ethz.journal.title
EMBO Molecular Medicine
ethz.journal.volume
4
en_US
ethz.journal.issue
10
en_US
ethz.journal.abbreviated
EMBO Mol Med
ethz.pages.start
1032
en_US
ethz.pages.end
1042
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.grant
More Medicines for Tuberculosis
en_US
ethz.identifier.wos
ethz.identifier.nebis
005874008
ethz.publication.place
Weinheim
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03647 - Altmann, Karl-Heinz / Altmann, Karl-Heinz
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03647 - Altmann, Karl-Heinz / Altmann, Karl-Heinz
ethz.grant.agreementno
260872
ethz.grant.fundername
EC
ethz.grant.funderDoi
10.13039/501100000780
ethz.grant.program
FP7
ethz.date.deposited
2017-06-10T09:52:17Z
ethz.source
ECIT
ethz.identifier.importid
imp59364fd933b8115501
ethz.ecitpid
pub:91123
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-31T15:43:01Z
ethz.rosetta.lastUpdated
2019-08-20T13:32:25Z
ethz.rosetta.versionExported
true
ethz.COinS
ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.atitle=Towards%20a%20new%20tuberculosis%20drug:%20pyridomycin%20%E2%80%93%20nature's%20isoniazid&rft.jtitle=EMBO%20Molecular%20Medicine&rft.date=2012-10-01&rft.volume=4&rft.issue=10&rft.spage=1032&rft.epage=1042&rft.issn=1757-4676&1757-4684&rft.au=Hartkoorn,%20Ruben%20C.&Sala,%20Claudia&Neres,%20Jo%C3%A3o&Pojer,%20Florence&Magnet,%20Sophie&rft.genre=article&
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