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Chlorflavonin Targets Acetohydroxyacid Synthase Catalytic Subunit IlvB1 for Synergistic Killing of Mycobacterium tuberculosis
ACS Infectious Diseases ( IF 5.3 ) Pub Date : 2017-11-16 00:00:00 , DOI: 10.1021/acsinfecdis.7b00055
Nidja Rehberg 1 , Herve Sergi Akone 1, 2 , Thomas R. Ioerger 3 , German Erlenkamp 4 , Georgios Daletos 1 , Holger Gohlke 4 , Peter Proksch 1 , Rainer Kalscheuer 1
Affiliation  

The flavonoid natural compound chlorflavonin was isolated from the endophytic fungus Mucor irregularis, which was obtained from the Cameroonian medicinal plant Moringa stenopetala. Chlorflavonin exhibited strong growth inhibitory activity in vitro against Mycobacterium tuberculosis (MIC90 1.56 μM) while exhibiting no cytotoxicity toward the human cell lines MRC-5 and THP-1 up to concentrations of 100 μM. Mapping of resistance-mediating mutations employing whole-genome sequencing, chemical supplementation assays, and molecular docking studies as well as enzymatic characterization revealed that chlorflavonin specifically inhibits the acetohydroxyacid synthase catalytic subunit IlvB1, causing combined auxotrophies to branched-chain amino acids and to pantothenic acid. While exhibiting a bacteriostatic effect in monotreatment, chlorflavonin displayed synergistic effects with the first-line antibiotic isoniazid and particularly with delamanid, leading to a complete sterilization in liquid culture in combination treatment. Using a fluorescent reporter strain, intracellular activity of chlorflavonin against Mycobacterium tuberculosis inside infected macrophages was demonstrated and was superior to streptomycin treatment.

中文翻译:

氯黄酮靶向乙酰羟酸合酶催化亚基IlvB1协同杀死结核分枝杆菌

从喀麦隆药用植物辣木(Moringa stenopetala)的内生真菌不规则毛鼠中分离出类黄酮天然化合物氯黄酮。氯黄酮在体外结核分枝杆菌具有很强的生长抑制活性(MIC 90浓度为100μM时对人细胞系MRC-5和THP-1没有细胞毒性,而对细胞的MRC-5和THP-1则无细胞毒性。使用全基因组测序,化学补充测定和分子对接研究以及酶促表征,对介导抗性的突变进行作图表明,氯黄酮特别抑制乙酰羟酸合酶催化亚基IlvB1,导致营养缺陷型合并为营养缺陷型分支链氨基酸和泛酸。氯黄酮在单次处理中表现出抑菌作用,但与一线抗生素异烟肼,尤其是与德拉曼尼德合用,表现出协同作用,从而在组合培养中在液体培养中实现了完全灭菌。使用荧光报告株,氯黄酮的细胞内活性事实证明,感染的巨噬细胞内的结核分枝杆菌优于链霉素。
更新日期:2017-11-16
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