Merck

Lansoprazole is an antituberculous prodrug targeting cytochrome bc1.

Nature communications (2015-07-15)
Jan Rybniker, Anthony Vocat, Claudia Sala, Philippe Busso, Florence Pojer, Andrej Benjak, Stewart T Cole
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Omeprazole, solid
Sigma-Aldrich
2-Propanol, BioReagent, for molecular biology, ≥99.5%
Sigma-Aldrich
2-Propanol, BioUltra, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
2-Propanol, anhydrous, 99.5%
Sigma-Aldrich
2-Propanol, electronic grade, 99.999% trace metals basis
Sigma-Aldrich
Isopropyl alcohol, ≥99.7%, FCC, FG
Sigma-Aldrich
Resorufin, 95%