期刊
ACS INFECTIOUS DISEASES
卷 5, 期 7, 页码 1239-1251出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00099
关键词
cholesterol; codrug; low oxygen
资金
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Disease of the National Institutes of Health [U01HL127522, R01AI134054, HHSN272201100009I]
- BEI Resources
- Center for Biotechnology, a New York State Center for Advanced Technology
- Stony Brook University
- Cold Spring Harbor Laboratory
- Brookhaven National Laboratory
- Feinstein Institute for Medical Research
- New York State Department of Economic Development [C14051]
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 mu M 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.
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