Unknown

Dataset Information

0

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.

SUBMITTER: Rybniker J 

PROVIDER: S-EPMC4510652 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

2020-01-01 | S-EPMC6999911 | BioStudies
2019-01-01 | S-EPMC6565617 | BioStudies
2018-01-01 | S-EPMC6299076 | BioStudies
1000-01-01 | S-EPMC5292992 | BioStudies
1000-01-01 | S-EPMC5514758 | BioStudies
2017-01-01 | S-EPMC5697821 | BioStudies
2013-01-01 | S-EPMC3535674 | BioStudies
2015-01-01 | S-EPMC4311836 | BioStudies
2014-01-01 | S-EPMC4028208 | BioStudies
2013-01-01 | S-EPMC3593749 | BioStudies