000184266 001__ 184266
000184266 005__ 20190316235556.0
000184266 0247_ $$2doi$$a10.1002/emmm.201201689
000184266 022__ $$a1757-4676
000184266 02470 $$2ISI$$a000309446200003
000184266 037__ $$aARTICLE
000184266 245__ $$aTowards a new tuberculosis drug: pyridomycin - nature's isoniazid
000184266 260__ $$bWiley Open Access$$c2012$$aHoboken
000184266 269__ $$a2012
000184266 300__ $$a11
000184266 336__ $$aJournal Articles
000184266 520__ $$aTuberculosis, 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.
000184266 6531_ $$adrug discovery
000184266 6531_ $$aInhA
000184266 6531_ $$aisoniazid
000184266 6531_ $$apyridomycin
000184266 6531_ $$atuberculosis
000184266 700__ $$0244368$$g183097$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aHartkoorn, Ruben C.
000184266 700__ $$0244366$$g179660$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aSala, Claudia
000184266 700__ $$0242076$$g196878$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aNeres, Joao
000184266 700__ $$0244369$$g180776$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aPojer, Florence
000184266 700__ $$0244367$$g181734$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aMagnet, Sophie
000184266 700__ $$0245571$$g212956$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aMukherjee, Raju
000184266 700__ $$g181909$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$aUplekar, Swapna$$0244370
000184266 700__ $$aBoy-Roettger, Stefanie$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$aAltmann, Karl-Heinz
000184266 700__ $$aCole, Stewart T.$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland$$g177247$$0243892
000184266 773__ $$j4$$tEmbo Molecular Medicine$$k10$$q1032-1042
000184266 8564_ $$uhttps://infoscience.epfl.ch/record/184266/files/1032.full.pdf$$zPublisher's version$$s472832$$yPublisher's version
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000184266 937__ $$aEPFL-ARTICLE-184266
000184266 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000184266 980__ $$aARTICLE