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Mce3R Stress-Resistance Pathway Is Vulnerable to Small-Molecule Targeting That Improves Tuberculosis Drug Activities
Xinxin Yang1, Tianao Yuan1, Rui Ma2
1Department of Chemistry , Stony Brook University , 100 John S. Toll Drive , Stony Brook , New York 11794-3400 , United States.
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.
Insights
New 6-azasteroid compounds sensitize Mycobacterium tuberculosis (Mtb) to existing drugs, offering a potential strategy to overcome drug tolerance and resistance in tuberculosis treatment.
Area of Science:
- Microbiology and Infectious Diseases
- Drug Discovery and Development
- Molecular Biology
Background:
- Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), affects one-third of the global population, with high mortality rates.
- Mtb can persist in a dormant state within host granulomas, with cholesterol playing a key role in its survival.
- Current TB treatments are lengthy, toxic, and require high drug doses, necessitating the development of novel therapeutic strategies.
Purpose of the Study:
- To identify novel compounds that can resensitize Mtb to existing TB drugs.
- To investigate the synergistic effects of identified compounds with established TB drugs like bedaquiline and isoniazid.
- To elucidate the molecular mechanisms underlying the activity of these novel compounds and their targets within Mtb.
Main Methods:
- Phenotypic screening of 35 6-azasteroid analogues against Mtb.
- Evaluation of bactericidal activity and drug synergy with bedaquiline and isoniazid under normoxic and hypoxic conditions.
- Analysis of Mtb resistance development and genetic basis of 6-azasteroid activity, focusing on the Mce3R regulon and cholesterol metabolism.
Main Results:
- A subset of 6-azasteroid analogues sensitized Mtb to multiple TB drugs at low micromolar concentrations.
- Two selected 6-azasteroids demonstrated strong synergy with bedaquiline, significantly reducing its minimal inhibitory concentration.
- Resistance to 6-azasteroids did not confer cross-resistance to bedaquiline or isoniazid, and activity was dependent on the Mce3R regulon, not cholesterol catabolism.
Conclusions:
- 6-Azasteroids are promising candidates for potentiating existing TB therapies, potentially shortening treatment duration and improving efficacy.
- The Mce3R regulon represents a novel drug target, mediating a cholesterol-regulated stress-resistance pathway crucial for Mtb pathogenesis and drug tolerance.
- Targeting this pathway with small molecules offers a viable strategy to combat persistent and drug-tolerant Mtb infections.
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