Lansoprazole is an antituberculous prodrug targeting cytochrome bc1

Jan Rybniker, Anthony Vocat, Claudia Sala, Philippe Busso, Florence Pojer, Andrej Benjak and Stewart T. Cole ()
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Jan Rybniker: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Anthony Vocat: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Claudia Sala: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Philippe Busso: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Florence Pojer: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Andrej Benjak: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)
Stewart T. Cole: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL)

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: Abstract Better 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 bc1 complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc1 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.

Date: 2015
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DOI: 10.1038/ncomms8659

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