Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development
Lipid transport in Mycobacterium tuberculosis and its implications in virulence and drug development
复制标题
DOI：
10.1016/j.bcp.2015.05.001
复制
发表时间：
2015-08-01
影响因子：
5.8
通讯作者：
Ainsa, Jose A.
中科院分区：
文献类型：
--
作者：
Bailo, Rebeca;Bhatt, Apoorva;Ainsa, Jose A.
结核病仍然是世界范围内的一个主要健康问题，也是单一传染源造成死亡的主要原因之一。只有少数药物真正有效地治疗结核病，因此，出现了多种，广泛和完全耐药杆菌妥协已经困难的抗结核治疗。鉴于结核病的持续全球负担，为了为开发更好的治疗和预防结核病的药物和策略铺平道路，了解结核病的致病因子结核分枝杆菌（Mtb）的致病性所需的潜在机制至关重要。已知在致病机制中起重要作用的是二乙酰基海藻糖（TMM，TDM）、邻苯二甲酸二酯（PDIM）、硫脂-1（SL-1）、二酰基海藻糖（DAT）和五酰基海藻糖（PAT）等;因此，负责其转运的蛋白质是潜在的毒力因子。MmpL和MmpS蛋白介导重要的细胞壁脂质跨分枝杆菌膜的转运。在Mtb中，MmpL 3、MmpL 7和MmpL 8分别转运TMM、PDIM和SL-1。DAT的易位和PAT的生物合成可能是由于MmpL 10。MmpL和MmpS蛋白参与其他过程，如药物外排（MmpL 5和MmpL 7）、铁载体输出（MmpL 4/MmpS 4和MmpL 5/MmpS 5）和血红素摄取（MmpL 3和MmpL 11）。总之，这些蛋白质可以被视为抗结核药物开发的新的潜在靶点。我们将回顾MmpL蛋白抑制剂开发的最新进展，在具有挑战性的背景下，针对膜蛋白和潜在的抗结核药物候选人的未来前景。(C)2015 Elsevier Inc. All rights reserved.
Tuberculosis is still a major health problem worldwide and one of the main causes of death by a single infectious agent. Only few drugs are really effective to treat tuberculosis, hence, the emergence of multiple, extensively, and totally drug resistant bacilli compromises the already difficult antituberculosis treatments. Given the persistent global burden of tuberculosis, it is crucial to understand the underlying mechanisms required for the pathogenicity of Mycobacterium tuberculosis (Mtb), the causal agent of tuberculosis, in order to pave the way for developing better drugs and strategies to treat and prevent tuberculosis.The exclusive mycobacterial cell wall lipids such as trehalose monomycolate and dimycolate (TMM, TDM), phthiocerol dimycocerosate (PDIM), sulpholipid-1 (SL-1), diacyl trehalose (DAT), and pentacyl trehalose (PAT), among others, are known to play an important role in pathogenesis; thus, proteins responsible for their transport are potential virulence factors. MmpL and MmpS proteins mediate transport of important cell wall lipids across the mycobacterial membrane. In Mtb, MmpL3, MmpL7 and MmpL8 transport TMM, PDIM and SL-1 respectively. The translocation of DAT and biosynthesis of PAT is likely due to MmpL10. MmpL and MmpS proteins are involved in other processes such as drug efflux (MmpL5 and MmpL7), siderophore export (MmpL4/MmpS4 and MmpL5/MmpS5), and heme uptake (MmpL3 and MmpL11). Altogether, these proteins can be regarded as new potential targets for antituberculosis drug development. We will review recent advances in developing inhibitors of MmpL proteins, in the challenging context of targeting membrane proteins and the future prospects for potential antituberculosis drug candidates. (C) 2015 Elsevier Inc. All rights reserved.