Association of mycothiol with protection of Mycobacterium tuberculosis from toxic oxidants and antibiotics
Association of mycothiol with protection of Mycobacterium tuberculosis from toxic oxidants and antibiotics
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DOI：
10.1046/j.1365-2958.2003.03416.x
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发表时间：
2003-03-01
影响因子：
3.6
通讯作者：
Fahey, RC
中科院分区：
文献类型：
--
作者：
Buchmeier, NA;Newton, GL;Fahey, RC
Mycothiol，MSH或1d-肌-肌醇2-（N -乙酰基-L-半胱氨酰）氨基-2-脱氧-α-d-吡喃葡萄糖苷，是N -乙酰半胱氨酸（AcCys）与1d-肌-肌醇2-乙酰氨基-2-脱氧-α-d-吡喃葡萄糖苷（GlcN-Ins）的不常见缀合物，是分枝杆菌中主要的低分子量硫醇。真菌硫醇具有抗氧化活性以及解毒多种有毒化合物的能力。由于这些活性，MSH是保护结核分枝杆菌在感染过程中不被宿主灭活以及抵抗抗结核药物的候选物。为了明确MSH对M.结核病，我们已经建立了一个M。Rv 1170是MSH生物合成候选基因之一。在指数生长期间，Rv 1170突变细菌产生的MSH水平约为野生型的20%。Rv 1170底物GlcNAc-Ins的水平升高，而产物GlcN-Ins的水平降低。这确定Rv 1170基因编码M的MSH生物合成途径中的主要GlcNAc-Ins脱乙酰酶活性（称为MshB）。结核Rv 1170突变体在缺乏过氧化氢酶和油酸的琼脂培养基上生长不佳，并且对有毒氧化剂氢过氧化枯烯和抗生素利福平的敏感性提高。此外，突变体更耐异烟肼，这表明MSH在激活这种前药的作用。这些数据表明，MSH有助于保护M。结核病从氧化剂和影响耐药性的两个一线抗结核药物。
Mycothiol, MSH or 1d-myo -inosityl 2-(N -acetyl-L-cysteinyl)amido-2-deoxy-alpha-d-glucopyranoside, is an unusual conjugate of N -acetylcysteine (AcCys) with 1d-myo-inosityl 2-acetamido-2-deoxy-alpha-d-glucopyranoside (GlcN-Ins), and is the major low-molecular-mass thiol in mycobacteria. Mycothiol has antioxidant activity as well as the ability to detoxify a variety of toxic compounds. Because of these activities, MSH is a candidate for protecting Mycobacterium tuberculosis from inactivation by the host during infections as well as for resisting antituberculosis drugs. In order to define the protective role of MSH for M. tuberculosis , we have constructed an M. tuberculosis mutant in Rv1170, one of the candidate MSH biosynthetic genes. During exponential growth, the Rv1170 mutant bacteria produced approximate to 20% of wild-type levels of MSH. Levels of the Rv1170 substrate, GlcNAc-Ins, were elevated, whereas those of the product, GlcN-Ins, were reduced. This establishes that the Rv1170 gene encodes for the major GlcNAc-Ins deacetylase activity (termed MshB) in the MSH biosynthetic pathway of M. tuberculosis. The Rv1170 mutant grew poorly on agar media lacking catalase and oleic acid, and had heightened sensitivities to the toxic oxidant cumene hydroperoxide and to the antibiotic rifampin. In addition, the mutant was more resistant to isoniazid, suggesting a role for MSH in activation of this prodrug. These data indicate that MSH contributes to the protection of M. tuberculosis from oxidants and influences resistance to two first-line antituberculosis drugs.