Mdluli K, Swanson J, Fischer E, Lee R E, Barry C E
Tuberculosis Research Unit, Rocky Mountain Laboratories, National Institutes of Health, National Institutes for Allergy and Infectious Diseases, Hamilton, MT 59840, USA.
Mol Microbiol. 1998 Mar;27(6):1223-33. doi: 10.1046/j.1365-2958.1998.00774.x.
Isoniazid (INH), which acts by inhibiting mycolic acid biosynthesis, is very potent against the tuberculous mycobacteria. It is about 100-fold less effective against Mycobacterium avium. This difference has often been attributed to a decreased permeability of the cell wall. We measured the rate of conversion of radiolabelled INH to 4-pyridylmethanol by whole cells and cell-free extracts and estimated the permeability barrier imposed by the cell wall to INH influx in Mycobacterium tuberculosis and M. avium. There was no significant difference in the relative permeability to INH between these two species. However, the total conversion rate in M. tuberculosis was found to be four times greater. Examination of in vitro-generated mutants revealed that the major resistance mechanism for both species is loss of the catalase-peroxidase KatG. Analysis of lipid and protein biosynthetic profiles demonstrated that the molecular target of activated INH was identical for both species. M. avium, however, formed colonies at INH concentrations inhibitory for mycolic acid biosynthesis. These mycolate-deficient M. avium exhibited altered colony morphologies, modified cell wall ultrastructure and were 10-fold more sensitive to treatment with hydrophobic antibiotics, such as rifampin. These findings may significantly impact the design of new therapeutic regimens for the treatment of infections with atypical mycobacteria.
异烟肼（INH）通过抑制分枝菌酸生物合成发挥作用，对结核分枝杆菌非常有效。它对鸟分枝杆菌的效力约低100倍。这种差异通常归因于细胞壁通透性降低。我们通过全细胞和无细胞提取物测量了放射性标记的INH转化为4 - 吡啶甲醇的速率，并估计了细胞壁对结核分枝杆菌和鸟分枝杆菌中INH流入所施加的通透性屏障。这两个菌种对INH的相对通透性没有显著差异。然而，发现结核分枝杆菌中的总转化率高四倍。对体外产生的突变体的检查表明，这两个菌种的主要耐药机制是过氧化氢酶 - 过氧化物酶KatG的缺失。对脂质和蛋白质生物合成谱的分析表明，活化的INH的分子靶点对这两个菌种是相同的。然而，鸟分枝杆菌在抑制分枝菌酸生物合成的INH浓度下形成菌落。这些缺乏分枝菌酸的鸟分枝杆菌表现出改变的菌落形态、修饰的细胞壁超微结构，并且对疏水性抗生素如利福平的治疗敏感性高10倍。这些发现可能会对治疗非典型分枝杆菌感染的新治疗方案的设计产生重大影响。
