Amity Institute of Biotechnology, Amity University Haryana, Gurugram, Manesar, 122413, India.
Biometals. 2019 Feb;32(1):49-63. doi: 10.1007/s10534-018-0157-8. Epub 2018 Nov 15.
Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is a global threat to human health hence better understanding of the MTB pathogenesis for improved therapeutics requires immediate attention. Emergence of drug-resistant strains has stimulated an urgent need for adopting new strategies that could be implemented to control TB. One of the contributing mechanisms by which MTB evades drug doses is overexpression of drug efflux pumps. Thus blocking or modulating the functionality of efflux pumps represents an attractive approach to combat drug resistance. Iron is a critical micronutrient required for MTB survival and not freely available inside the host. In this study, we demonstrated that iron deprivation impairs drug efflux pump activity and confers synergism for anti-TB drugs in presence of efflux pump inhibitors against MTB. Mechanistic insights revealed that iron deprivation inhibit resistance nodulation division superfamily transporter activity. This was evident from enhanced Nile red accumulation and reduced expression of MmpL3, a transmembrane promising target involved in mycolic acid transport across membrane. Furthermore, iron deprivation led to abrogated MA transport particularly of class methoxy-MA which was confirmed by TLC and mass spectrometry based lipidome analysis. Additionally, iron deprivation leads to enhanced membrane fluidity in MTB. Together, MmpL3 being a promiscuous anti-TB target, metal chelation strategy could be adopted to boost the effectiveness of current anti-TB drug regimes to combat drug resistance TB.
结核分枝杆菌（MTB）引起的结核病是对人类健康的全球性威胁，因此，为了改善治疗效果，迫切需要更好地了解 MTB 的发病机制。耐药菌株的出现刺激了急需采用新策略来控制结核病。MTB 逃避药物剂量的一个重要机制是过度表达药物外排泵。因此，阻断或调节外排泵的功能代表了一种有吸引力的对抗耐药性的方法。铁是 MTB 生存所必需的关键微量营养素，在宿主体内不易获得。在这项研究中，我们证明了铁剥夺会损害药物外排泵的活性，并在存在外排泵抑制剂的情况下增强抗结核药物的协同作用。机制研究表明，铁剥夺抑制了耐药结节分裂超家族转运蛋白的活性。这可以从 Nile red 积累增加和 MmpL3 表达减少得到证明，MmpL3 是一种跨膜蛋白，参与分枝菌酸的跨膜运输，是一种有前途的靶标。此外，铁剥夺会导致 MA 转运减少，特别是类甲氧基-MA，这可以通过 TLC 和基于质谱的脂质组学分析来证实。此外，铁剥夺会导致 MTB 中的膜流动性增加。总之，MmpL3 是一种混杂的抗结核靶点，金属螯合策略可以用来提高现有抗结核药物治疗方案的效果，以对抗耐药性结核病。
