Mce3R stress-resistance pathway is vulnerable to small-molecule targeting that improves tuberculosis drug activities
Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
American Chemical Society
Abstract
One-third of the world’s population carries Mycobacterium tuberculosis
(Mtb), the infectious agent that causes tuberculosis (TB), and every 17 s
someone dies of TB. After infection, Mtb can live dormant for decades in a
granuloma structure arising from the host immune response, and cholesterol is
important for this persistence of Mtb. Current treatments require long-duration
drug regimens with many associated toxicities, which are compounded by the high
doses required. We phenotypically screened 35 6-azasteroid analogues against Mtb
and found that, at low micromolar concentrations, a subset of the analogues
sensitized Mtb to multiple TB drugs. Two analogues were selected for further study
to characterize the bactericidal activity of bedaquiline and isoniazid under normoxic
and low-oxygen conditions. These two 6-azasteroids showed strong synergy with
bedaquiline (fractional inhibitory concentration index = 0.21, bedaquiline minimal
inhibitory concentration = 16 nM at 1 μM 6-azasteroid). The rate at which
spontaneous resistance to one of the 6-azasteroids arose in the presence of bedaquiline was approximately 10−9, and the 6-
azasteroid-resistant mutants retained their isoniazid and bedaquiline sensitivity. Genes in the cholesterol-regulated Mce3R
regulon were required for 6-azasteroid activity, whereas genes in the cholesterol catabolism pathway were not. Expression of a
subset of Mce3R genes was down-regulated upon 6-azasteroid treatment. The Mce3R regulon is implicated in stress resistance
and is absent in saprophytic mycobacteria. This regulon encodes a cholesterol-regulated stress-resistance pathway that we
conclude is important for pathogenesis and contributes to drug tolerance, and this pathway is vulnerable to small-molecule
targeting in live mycobacteria.
Description
CITATION: Yang, X., et. al. 2019. Mce3R stress-resistance pathway is vulnerable to small-molecule targeting that improves tuberculosis drug activities. ACS Infectious Diseases, 5(7):1239-1251, doi:10.1021/acsinfecdis.9b00099.
The original publication is available at https://pubs.acs.org
The original publication is available at https://pubs.acs.org
Keywords
Mycobacterium tuberculosis -- Drug testing, Repressors, Genetic, Isoniazid, Bedaquiline
Citation
Yang, X., et. al. 2019. Mce3R stress-resistance pathway is vulnerable to small-molecule targeting that improves tuberculosis drug activities. ACS Infectious Diseases, 5(7):1239-1251, doi:10.1021/acsinfecdis.9b00099