The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis
The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis
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DOI：
10.1086/340577
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发表时间：
2002-06-01
影响因子：
6.4
通讯作者：
Sims, PFG
中科院分区：
文献类型：
--
作者：
Aspinall, TV;Joynson, DHM;Sims, PFG
对刚地弓形虫二氢蝶酸合酶基因（dhps）进行聚合酶链反应扩增和DNA测序，在32例人类弓形虫病的寄生虫种群中鉴定出4个等位基因。异源表达和酶活性测定显示，其中3个等位基因编码对磺胺嘧啶（Sdz）敏感的酶。第4个等位基因产生一种对Sdz高度耐药的酶，它与另外3个等位基因中的1个仅在二氢蝶酸合酶（DHPS）的一个单一残基（407位）上存在差异。有趣的是，在实验室诱导的磺胺嘧啶耐药株中发现的第5个等位基因，也因影响DHPS的407位残基的相同单一突变而与这3种药物敏感形式中的另一种不同。重要的是，与DHPS - 407相对应的残基与其他微生物中的磺胺类药物耐药性有关。编码对Sdz耐药的酶的人源等位基因形式在与致命感染相关的刚地弓形虫中被发现，它在临床样本中的存在可能对磺胺类药物的使用产生影响，特别是在对药物治疗初始反应不佳的弓形虫病病例中。
Polymerase chain reaction amplification and DNA sequencing of the Toxoplasma gondii dihydropteroate synthase gene (dhps) identified 4 alleles among parasite populations from 32 cases of human toxoplasmosis. Heterologous expression and enzyme assay reveal that 3 of these alleles encode sulfadiazine (Sdz)-sensitive enzymes. The fourth, generating a highly Sdz-resistant enzyme, differs from 1 of the other 3 at only a single residue (407) of DHPS. Of interest, a fifth allele, found in a laboratory-induced Sdz-resistant line, also differs from another of these 3 drug-sensitive forms by the same single mutation that affects residue 407 of DHPS. Significantly, residues corresponding to DHPS-407 are implicated in sulfonamide resistance in other microorganisms. The human-derived allelic form encoding the Sdz-resistant enzyme was found in T. gondii associated with a fatal infection, and its presence within clinical material may have implications for sulfonamide use, particularly in cases of toxoplasmosis in which the initial response to drug treatment is poor.