title: Lansoprazole is an antituberculous prodrug targeting cytochrome bc1.
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.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.|1st Department of Internal Medicine, University of Cologne, D-50937 Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Rybniker
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vocat
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Busso
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Pojer
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Andrej
authors.identifier: http://orcid.org/0000-0003-4522-6575
authors.initials: A
authors.lastname: Benjak
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery / Q000379:methods; D024881:Drug Resistance, Bacterial; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000187:drug effects*; D005347:Fibroblasts; D057166:High-Throughput Screening Assays; D006801:Humans; D064747:Lansoprazole / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009853:Omeprazole; D000077402:Pantoprazole; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D013440:Sulfides / Q000378:metabolism / Q000494:pharmacology; D018088:Tuberculosis, Multidrug-Resistant
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000995:Antitubercular Agents; D011355:Prodrugs; D054328:Proton Pump Inhibitors; D013440:Sulfides; D064747:Lansoprazole; D000077402:Pantoprazole; D014450:Electron Transport Complex III; D009853:Omeprazole