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ACS Infect Dis. 2019 Jul 12;5(7):1239-1251. doi: 10.1021/acsinfecdis.9b00099. Epub 2019 May 3.

Mce3R Stress-Resistance Pathway Is Vulnerable to Small-Molecule Targeting That Improves Tuberculosis Drug Activities.

Author information

1
Department of Chemistry , Stony Brook University , 100 John S. Toll Drive , Stony Brook , New York 11794-3400 , United States.
2
Institute for Tuberculosis Research , University of Illinois at Chicago , 833 South Wood Street, 425 PHARM , Chicago , Illinois 60612-7231 , United States.
3
Department of Genetics and Genomic Sciences , Icahn School of Medicine at Mount Sinai , One Gustave L. Levy Place , Box 1498, New York City , New York 10029 , United States.
4
Icahn Institute for Genomics and Multiscale Biology , Icahn School of Medicine at Mount Sinai , One Gustave L. Levy Place , Box 1498, New York City , New York , 10029-6574 , United States.
5
Institute of Chemical Biology and Drug Discovery , Stony Brook University , 100 John S. Toll Drive , Stony Brook , New York 11794-3400 , United States.
6
Stellenbosch Institute for Advanced Study (STIAS) , Wallenberg Research Centre at Stellenbosch University , 10 Marais Street , Stellenbosch 7600 , South Africa.

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.

KEYWORDS:

cholesterol; codrug; low oxygen

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