Koen Nadia, van Breda Shane Vontelin, Loots Du Toit
Human Metabolomics, North-West University, Private Bag x6001, Box 269, Potchefstroom, 2531, South Africa.
Department of Internal Medicine, Division of Infectious Diseases, University of Pretoria, Pretoria, 0002, South Africa.
Tuberculosis (Edinb). 2018 Jul;111:154-160. doi: 10.1016/j.tube.2018.06.008. Epub 2018 Jun 13.
Over the past 5 years, there has been a renewed interest in finding new compounds with anti-TB action. Colistin methanesulfonate or polymyxin E, is a possible anti-TB drug candidate, which may in future be used either alone or in combination to the current 6 month "directly observed treatment short-course" (DOTS) regimen. However its mechanism of action has to date not yet been fully explored, and only described from a histological and genomics perspective. Considering this, we used a GCxGC-TOFMS metabolomics approach and identified those metabolite markers characterising Mycobacterium tuberculosis (Mtb) cultured in the presence of colistin methanesulfonate, in order to better understand or confirm its mechanism of action. The metabolite markers identified indicated a flux in the metabolism of the colistin methanesulfonate treated Mtb towards fatty acid synthesis and cell wall repair, confirming previous reports that colistin acts by disrupting the cell wall of mycobacteria. Accompanying this, is a subsequently elevated glucose uptake, since the latter now serves as the primary energy substrate for the upregulated glyoxylate cycle, and additionally as a precursor for further fatty acid synthesis via the glycerolipid metabolic pathway. Furthermore, the elevated concentrations of those metabolites associated with pentose phosphate, valine, threonine, and pentanediol metabolism, also confirms a shift towards glucose utilization for energy production, in the colistin methanesulfonate treated Mtb.
在过去5年里，人们对寻找具有抗结核作用的新化合物重新产生了兴趣。黏菌素甲磺酸盐或多黏菌素E是一种可能的抗结核药物候选物，未来可能单独使用或与目前的6个月“直接观察短程治疗”（DOTS）方案联合使用。然而，其作用机制迄今为止尚未得到充分探索，仅从组织学和基因组学角度进行了描述。考虑到这一点，我们采用了全二维气相色谱-飞行时间质谱代谢组学方法，鉴定了在黏菌素甲磺酸盐存在下培养的结核分枝杆菌（Mtb）的代谢物标志物，以便更好地理解或确认其作用机制。鉴定出的代谢物标志物表明，经黏菌素甲磺酸盐处理的Mtb的代谢朝着脂肪酸合成和细胞壁修复方向流动，这证实了先前关于黏菌素通过破坏分枝杆菌细胞壁起作用的报道。与此同时，葡萄糖摄取随后增加，因为后者现在作为上调的乙醛酸循环的主要能量底物，并且还作为通过甘油脂质代谢途径进一步合成脂肪酸的前体。此外，与磷酸戊糖、缬氨酸、苏氨酸和戊二醇代谢相关的那些代谢物浓度升高，也证实了在经黏菌素甲磺酸盐处理的Mtb中，朝着利用葡萄糖产生能量的方向转变。
