The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria
The folate pathway is a target for resistance to the drug para-aminosalicylic acid (PAS) in mycobacteria
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DOI：
10.1111/j.1365-2958.2004.04120.x
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发表时间：
2004-07-01
影响因子：
3.6
通讯作者：
Rubin, EJ
中科院分区：
文献类型：
--
作者：
Rengarajan, J;Sassetti, CM;Rubin, EJ
耐多药结核病发病率的增加导致对氨基水杨酸（PAS）等二线抗生素的使用增加。PAS的作用方式尚不清楚，对这种药物的耐药机制也不明确。我们已经分离出PAS抗性转座子突变体的牛分枝杆菌BCG插入胸苷酸合成酶（thyA）基因，细胞内叶酸水平的一个关键决定因素。BCG thyA突变体具有降低的胸苷酸合成酶活性，并且对已知的叶酸途径抑制剂具有抗性。我们还发现thyA基因突变与临床PAS耐药相关。我们已经从感染患者中鉴定出PAS耐药结核分枝杆菌分离株，其在thyA中具有突变并显示编码酶的活性降低。因此，PAS在叶酸途径中起作用，thyA突变可能代表了不仅对PAS而且对其他靶向叶酸代谢的药物产生耐药性的机制。
The increasing rate of multidrug-resistant tuberculosis has led to more use of second-line antibiotics such as para-aminosalicylic acid (PAS). The mode of action of PAS remains unclear, and mechanisms of resistance to this drug are undefined. We have isolated PAS-resistant transposon mutants of Mycobacterium bovis BCG with insertions in the thymidylate synthase (thyA) gene, a critical determinant of intracellular folate levels. BCG thyA mutants have reduced thymidylate synthase activity and are resistant to known inhibitors of the folate pathway. We also find that mutations in thyA are associated with clinical PAS resistance. We have identified PAS-resistant Mycobacterium tuberculosis isolates from infected patients, which harbour mutations in thyA and show reduced activity of the encoded enzyme. Thus, PAS acts in the folate pathway, and thyA mutations probably represent a mechanism of developing resistance not only to PAS but also to other drugs that target folate metabolism.