International Journal of Medical Microbiology ( IF 4.1 ) Pub Date : 2019-06-24 , DOI: 10.1016/j.ijmm.2019.06.003 Jiao Zhao 1 , Wenjing Wei 2 , Huimin Yan 3 , Ying Zhou 4 , Zhenyan Li 5 , Yanmei Chen 2 , Chenchen Zhang 2 , Jincheng Zeng 3 , Tao Chen 6 , Lin Zhou 7
Capreomycin (CAP), a cyclic peptide antibiotic, is considered to be an ideal second-line drug for tuberculosis (TB). However, in the past few years, the emergence of more CAP-resistant (CAPr) TB patients has limited its use. Although it has been reported that CAP resistance to Mycobacterium tuberculosis (Mtb) is associated with rrs or tlyA mutation, the exact mechanism of CAPr Mtb strains, especially the mechanism associated with tlyA deficient or mutation, is not fully understood. Herein, we utilized a multi-omics (genome, proteome, and metabolome) approach to assess CAP resistance on tlyA deficient CAPr Mtb strains (CAPr1) and tlyA point mutation CAPr Mtb strains (CAPr2) that we established for the first time in vitro to investigate the CAP-resistant mechanism. Our results showed that the CAPr1 strains (> 40 μg/ml) was more resistant to CAP than the CAPr2 strains (G695A, 10 μg/ml). Furthermore, multi-omics analysis indicated that the CAPr1 strains exhibited greater drug tolerance than the CAPr2 strains may be associated with the weakening of S-adenosyl-L-methionine-dependent methyltransferase (AdoMet-MT) activity and abnormal membrane lipid metabolism such as suppression of fatty acid metabolism, promotion of glycolipid phospholipid and glycerolipid metabolism. As a result, these studies reveal a new mechanism for CAP resistance to tlyA deficient or mutation Mtb strains, and may be helpful in developing new therapeutic approaches to prevent Mtb resistance to CAP.
中文翻译:
使用多组学分析评估tlyA缺陷和点突变(G695A)结核分枝杆菌菌株对卡普霉素的耐药性。
环肽抗生素Capreomycin(CAP)被认为是治疗肺结核(TB)的理想二线药物。但是,在过去的几年中,更多的CAP耐药(CAP r)结核病患者的出现限制了它的使用。尽管已经报道CAP对结核分枝杆菌(Mtb)的抗性与rrs或tlyA突变有关,但CAP r Mtb菌株的确切机制,特别是与tlyA缺陷或突变有关的机制尚不完全清楚。本文中,我们利用多组学(基因组,蛋白质组和代谢组学)方法评估了tlyA缺陷型CAP r Mtb菌株(CAP )的CAP耐药性。r 1)和我们首次在体外建立的tlyA点突变CAP r Mtb菌株(CAP r 2),以研究CAP耐药机制。我们的结果表明,CAP r 1菌株(> 40μg/ ml)比CAP r 2菌株(G695A,10μg/ ml)对CAP的抵抗力更高。此外,多组学分析表明,该CAP - [R 1菌株表现出比CAP更大的药物耐受性ř2个菌株可能与S-腺苷-L-蛋氨酸依赖性甲基转移酶(AdoMet-MT)活性减弱和膜脂代谢异常有关,例如抑制脂肪酸代谢,促进糖脂磷脂和甘油脂代谢。结果,这些研究揭示了CAP对tlyA缺陷或突变的Mtb菌株的抗性的新机制,并且可能有助于开发新的预防Mtb对CAP的抗性的治疗方法。