Mce3R 抗压通路易受可改善结核病药物活性的小分子靶向作用。,ACS Infectious Diseases

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Mce3R 抗压通路易受可改善结核病药物活性的小分子靶向作用。
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-05-03 , DOI: 10.1021/acsinfecdis.9b00099
Xinxin Yang ₁ , Tianao Yuan ₁ , Rui Ma ₂ , Kieran I Chacko ₃ , Melissa Smith _{3,

4} , Gintaras Deikus _{3,

4} , Robert Sebra _{3,

4} , Andrew Kasarskis _{3,

4} , Harm van Bakel _{3,

4} , Scott G Franzblau ₂ , Nicole S Sampson _{1,

5,

6}

Affiliation

世界上三分之一的人口携带结核分枝杆菌 (Mtb)，这是导致结核病 (TB) 的传染源，每 17 秒就有一个人死于结核病。感染后，Mtb 可以在宿主免疫反应引起的肉芽肿结构中休眠数十年，而胆固醇对于 Mtb 的这种持续存在很重要。目前的治疗需要长期的药物治疗方案，并伴随着许多相关的毒性，而所需的高剂量又加剧了这种情况。我们按表型筛选了 35 种抗 Mtb 的 6-氮杂类固醇类似物，发现在低微摩尔浓度下，部分类似物使 Mtb 对多种结核病药物敏感。选择了两种类似物进行进一步研究，以表征贝达喹啉和异烟肼在常氧和低氧条件下的杀菌活性。这两种 6-氮杂类固醇与贝达喹啉显示出很强的协同作用（分数抑制浓度指数 = 0.21，贝达喹啉最小抑制浓度 = 16 nM，1 μM 6-氮杂类固醇）。在存在贝达喹啉的情况下，对 6-氮杂类固醇之一的自发耐药率约为 10-9，并且 6-氮杂类固醇耐药突变体保留了它们对异烟肼和贝达喹啉的敏感性。胆固醇调节的 Mce3R 调节子中的基因是 6-氮杂类固醇活性所必需的，而胆固醇分解代谢途径中的基因则不需要。Mce3R 基因子集的表达在 6-氮杂类固醇处理后下调。Mce3R 调节子与抗逆性有关，在腐生分枝杆菌中不存在。

"点击查看英文标题和摘要"

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

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.

更新日期：2019-04-23

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