000184266 001__ 184266
000184266 005__ 20180317093652.0
000184266 0247_ $$2doi$$a10.1002/emmm.201201689
000184266 022__ $$a1757-4676
000184266 02470 $$2ISI$$a000309446200003
000184266 037__ $$aARTICLE
000184266 245__ $$aTowards a new tuberculosis drug: pyridomycin - nature's isoniazid
000184266 260__ $$aHoboken$$bWiley Open Access$$c2012
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$$aHartkoorn, Ruben C.$$g183097$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$0244366$$aSala, Claudia$$g179660$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$0242076$$aNeres, Joao$$g196878$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$0244369$$aPojer, Florence$$g180776$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$0244367$$aMagnet, Sophie$$g181734$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$0245571$$aMukherjee, Raju$$g212956$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$0244370$$aUplekar, Swapna$$g181909$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$aBoy-Roettger, Stefanie$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 700__ $$aAltmann, Karl-Heinz
000184266 700__ $$0243892$$aCole, Stewart T.$$g177247$$uEcole Polytech Fed Lausanne, Global Hlth Inst, Lausanne, Switzerland
000184266 773__ $$j4$$k10$$q1032-1042$$tEmbo Molecular Medicine
000184266 8564_ $$s472832$$uhttps://infoscience.epfl.ch/record/184266/files/1032.full.pdf$$yPublisher's version$$zPublisher's version
000184266 909CO $$ooai:infoscience.tind.io:184266$$particle$$pSV
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000184266 917Z8 $$x164606
000184266 917Z8 $$x164606
000184266 917Z8 $$x182396
000184266 937__ $$aEPFL-ARTICLE-184266
000184266 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000184266 980__ $$aARTICLE