Mce3R stress-resistance pathway is vulnerable to small-molecule targeting that improves tuberculosis drug activities

Yang, Xinxin ; Yuan, Tianao ; Ma, Rui ; Chacko, Kieran I. ; Smith, Melissa ; Deikus, Gintaras ; Sebra, Robert ; Kasarskis, Andrew ; Van Bakel, Harm ; Franzblau, Scott G. ; Sampson, Nicole S. (2019)

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.

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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.

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