Universität zu Köln

Rybniker, Jan, Vocat, Anthony, Sala, Claudia ORCID: 0000-0003-4031-4648, Busso, Philippe, Pojer, Florence, Benjak, Andrej ORCID: 0000-0003-4522-6575 and Cole, Stewart T. (2015). Lansoprazole is an antituberculous prodrug targeting cytochrome bc(1). Nat. Commun., 6. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

Full text not available from this repository.

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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Rybniker, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Vocat, Anthony UNSPECIFIED UNSPECIFIED UNSPECIFIED Sala, Claudia UNSPECIFIED orcid.org/0000-0003-4031-4648 UNSPECIFIED Busso, Philippe UNSPECIFIED UNSPECIFIED UNSPECIFIED Pojer, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED Benjak, Andrej UNSPECIFIED orcid.org/0000-0003-4522-6575 UNSPECIFIED Cole, Stewart T. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-399311
DOI:	10.1038/ncomms8659
Journal or Publication Title:	Nat. Commun.
Volume:	6
Date:	2015
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTON-PUMP INHIBITORS; MYCOBACTERIUM-TUBERCULOSIS; DRUG DISCOVERY; IDENTIFICATION; COMBINATION Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/39931