Knoll Kirsten E, Lindeque Zander, Adeniji Adetomiwa A, Oosthuizen Carel B, Lall Namrita, Loots Du Toit
Human Metabolomics, North-West University, Private Bag x6001, Box 269, Potchefstroom 2531, South Africa.
Department of Plant and Soil Sciences, Faculty of Natural and Agricultural Sciences, University of Pretoria, Pretoria 0002, South Africa.
Antibiotics (Basel). 2021 Jun 10;10(6):693. doi: 10.3390/antibiotics10060693.
Tuberculosis (TB), caused by (), still remains one of the leading causes of death from a single infectious agent worldwide. The high prevalence of this disease is mostly ascribed to the rapid development of drug resistance to the current anti-TB drugs, exacerbated by lack of patient adherence due to drug toxicity. The aforementioned highlights the urgent need for new anti-TB compounds with different antimycobacterial mechanisms of action to those currently being used. An -alkyl quinolone; decoquinate derivative RMB041, has recently shown promising antimicrobial activity against , while also exhibiting low cytotoxicity and excellent pharmacokinetic characteristics. Its exact mechanism of action, however, is still unknown. Considering this, we used GCxGC-TOFMS and well described metabolomic approaches to analyze and compare the metabolic alterations of treated with decoquinate derivative RMB041 by comparison to non-treated controls. The most significantly altered pathways in treated with this drug include fatty acid metabolism, amino acid metabolism, glycerol metabolism, and the urea cycle. These changes support previous findings suggesting this drug acts primarily on the cell wall and secondarily on the DNA metabolism of . Additionally, we identified metabolic changes suggesting inhibition of protein synthesis and a state of dormancy.
由（）引起的结核病（TB）仍然是全球单一感染源导致死亡的主要原因之一。这种疾病的高流行率主要归因于对当前抗结核药物耐药性的迅速发展，而药物毒性导致患者依从性差又加剧了这一情况。上述情况凸显了迫切需要研发具有与目前所用药物不同抗分枝杆菌作用机制的新型抗结核化合物。一种 - 烷基喹诺酮；癸氧喹酯衍生物RMB041，最近显示出对（）有良好的抗菌活性，同时还表现出低细胞毒性和优异的药代动力学特性。然而，其确切的作用机制仍然未知。考虑到这一点，我们使用气相色谱 - 飞行时间质谱联用（GCxGC - TOFMS）以及成熟的代谢组学方法，通过与未处理的（）对照进行比较，分析和比较用癸氧喹酯衍生物RMB041处理后的（）的代谢变化。用这种药物处理后的（）中变化最显著的途径包括脂肪酸代谢、氨基酸代谢、甘油代谢和尿素循环。这些变化支持了先前的研究结果，表明这种药物主要作用于（）的细胞壁，其次作用于其DNA代谢。此外，我们还确定了表明蛋白质合成受到抑制和处于休眠状态的代谢变化。
