Attenuation of Mycobacterium tuberculosis functionally disrupted in a fatty acyl-coenzyme A synthetase gene fadD5.
Attenuation of Mycobacterium tuberculosis functionally disrupted in a fatty acyl-coenzyme A synthetase gene fadD5.
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DOI：
10.1086/651452
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发表时间：
2010-04-15
期刊：
影响因子：
--
通讯作者：
Riley LW
中科院分区：
文献类型：
--
作者：
Dunphy KY;Senaratne RH;Masuzawa M;Kendall LV;Riley LW
结核分枝杆菌在体内长期生存的一个关键适应是依赖脂质作为能量来源。M.结核病H37 Rv具有36个fadD基因，注释为推定的脂肪酰基-CoA合成酶基因，其编码激活脂肪酸用于代谢的酶。一个这样的基因，fadD 5（Rv 0166），位于mce 1操纵子内，这是一组与M.结核病持续存在我们破坏了H37 RvM中fadD 5的假定脂肪酸结合位点。结核突变株和野生型菌株在营养丰富的肉汤或活化的RAW 264.7细胞中的体外生长没有显着差异。然而，fadD 5突变体在含有分枝菌酸的基本培养基中生长减少，但不含其他长链脂肪酸。感染fadD 5突变体的C57 BL/6小鼠的存活时间明显长于感染野生型的C57 BL/6小鼠，并且突变体从未达到小鼠肺部感染的平台期。稳态感染期维持了长达168天，水平比野生型低一到两个对数。这些观察结果提出了一个相当有趣的可能性，即FadD 5可能有助于结核杆菌长期存活的分枝菌酸的再循环。
One key adaptation that Mycobacterium tuberculosis established to survive long term in vivo is a reliance on lipids as an energy source. M. tuberculosis H37Rv has 36 fadD genes annotated as putative fatty acyl-CoA synthetase genes, which encode enzymes that activate fatty acids for metabolism. One such gene, fadD5 (Rv0166), is located within the mce1 operon, a cluster of genes associated with M. tuberculosis persistence. We disrupted the putative fatty acid binding site of fadD5 in H37Rv M. tuberculosis. No significant differences were found in the growth of the mutant and wild-type strains in vitro in nutrient-rich broth or in activated RAW264.7 cells. However, the fadD5 mutant was diminished in growth in minimal medium containing mycolic acid, but not other long-chain fatty acids. C57BL/6 mice infected with the fadD5 mutant survived significantly longer than those infected with wild-type, and the mutant never attained the plateau phase of infection in the mouse lungs. The steady-state infection phase was maintained for up to 168 days at a level one to two logs less than that shown by wild-type. These observations raise a rather intriguing possibility that FadD5 may serve to recycle mycolic acids for the long-term survival of the tubercle bacilli.
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