Pal Rahul, Hameed Saif, Kumar Parveen, Singh Sarman, Fatima Zeeshan
1Amity Institute of Biotechnology, Amity University Haryana, Manesar, Gurugram, 122413 India.
2Division of Clinical Microbiology and Molecular Medicine, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, 110029 India.
3 Biotech. 2019 Apr;9(4):122. doi: 10.1007/s13205-019-1645-4. Epub 2019 Mar 5.
Under limited micronutrients condition, (MTB) has to struggle for acquisition of the limited micronutrients available in the host. One such crucial micronutrient that MTB requires for the growth and sustenance is iron. The present study aimed to sequester the iron supply of MTB to control drug resistance in MTB. We found that iron restriction renders hypersensitivity to multidrug-resistant MTB strains against first-line anti-TB drugs. To decipher the effect of iron restriction on possible mechanisms of chemosensitization and altered cellular circuitry governing drug resistance and virulence of MTB, we explored MTB cellular architecture. We could identify non-intact cell envelope, tampered MTB morphology and diminished mycolic acid under iron restricted MDR-MTB cells. Deeper exploration unraveled altered lipidome profile observed through conventional TLC and advanced mass spectrometry-based LC-ESI-MS techniques. Lipidome analysis not only depicted profound alterations of various lipid classes which are crucial for pathogenecity but also exposed leads such as indispensability of iron to sustain metabolic, genotoxic and oxidative stresses. Furthermore, iron deprivation led to inhibited biofilm formation and capacity of MTB to adhere buccal epithelial cells. Lastly, we demonstrated enhanced survival of infected model under iron limitation. The present study offers evidence and proposes alteration of lipidome profile and affected virulence traits upon iron chelation. Taken together, iron deprivation could be a potential strategy to rescue MDR and enhance the effectiveness of existing anti-TB drugs.
在微量营养素有限的条件下，结核分枝杆菌（MTB）必须努力获取宿主体内有限的微量营养素。MTB生长和生存所必需的一种关键微量营养素是铁。本研究旨在阻断MTB的铁供应，以控制MTB的耐药性。我们发现，铁限制使多药耐药MTB菌株对一线抗结核药物产生超敏反应。为了阐明铁限制对MTB化学增敏的可能机制以及控制MTB耐药性和毒力的细胞信号通路改变的影响，我们探究了MTB的细胞结构。我们发现在铁限制的耐多药MTB细胞中，细胞包膜不完整、MTB形态改变以及分枝菌酸减少。进一步的探究揭示了通过传统薄层层析（TLC）和基于先进质谱的液相色谱-电喷雾电离质谱（LC-ESI-MS）技术观察到的脂质组谱变化。脂质组分析不仅描绘了对致病性至关重要的各种脂质类别的深刻变化，还揭示了一些线索，如铁对维持代谢、基因毒性和氧化应激的不可或缺性。此外，铁剥夺导致MTB生物膜形成受到抑制以及MTB黏附颊上皮细胞的能力下降。最后，我们证明了在铁限制条件下感染模型的存活率提高。本研究提供了证据，并提出了铁螯合后脂质组谱的改变和毒力特征的变化。综上所述，铁剥夺可能是挽救耐多药MTB并提高现有抗结核药物有效性的一种潜在策略。
