000212232 001__ 212232
000212232 005__ 20190317000303.0
000212232 0247_ $$2doi$$a10.1038/ncomms8659
000212232 022__ $$a2041-1723
000212232 02470 $$2ISI$$a000358858100003
000212232 037__ $$aARTICLE
000212232 245__ $$aLansoprazole is an antituberculous prodrug targeting cytochrome bc1
000212232 269__ $$a2015
000212232 260__ $$bNature Publishing Group$$c2015$$aLondon
000212232 300__ $$a8
000212232 336__ $$aJournal Articles
000212232 520__ $$aBetter antibiotics capable of killing multi-drug-resistant Mycobacterium tuberculosis are urgently needed. Despite extensive drug discovery efforts, only a few promising candidates are on the horizon and alternative screening protocols are required. Here, by testing a panel of FDA-approved drugs in a host cell-based assay, we show that the blockbuster drug lansoprazole (Prevacid), a gastric proton-pump inhibitor, has intracellular activity against M. tuberculosis. Ex vivo pharmacokinetics and target identification studies reveal that lansoprazole kills M. tuberculosis by targeting its cytochrome bc(1) complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc(1) inhibitors is highly active against drug-resistant clinical isolates and spares the human H+K+-ATPase thus providing excellent opportunities for targeting the major pathogen M. tuberculosis. Our finding provides proof of concept for hit expansion by metabolic activation, a powerful tool for antibiotic screens.
000212232 6531_ $$aBacteriology
000212232 6531_ $$aDrug screening
000212232 6531_ $$aPharmacokinetics
000212232 6531_ $$aTarget identification
000212232 700__ $$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$aRybniker, Jan
000212232 700__ $$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$aVocat, Anthony
000212232 700__ $$0244366$$g179660$$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$aSala, Claudia
000212232 700__ $$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$aBusso, Philippe
000212232 700__ $$0244369$$g180776$$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$aPojer, Florence
000212232 700__ $$0246601$$g229809$$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$aBenjak, Andrej
000212232 700__ $$aCole, Stewart T.$$uEcole Polytech Fed Lausanne, Global Hlth Inst, CH-1015 Lausanne, Switzerland$$g177247$$0243892
000212232 773__ $$j6$$tNature Communications$$q7659
000212232 8564_ $$uhttps://infoscience.epfl.ch/record/212232/files/ncomms8659.pdf$$zPublisher's version$$s4602694$$yPublisher's version
000212232 909C0 $$xU11742$$0252302$$pUPCOL
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000212232 917Z8 $$x217823
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000212232 937__ $$aEPFL-ARTICLE-212232
000212232 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000212232 980__ $$aARTICLE