ANTICOCCIDIAL DRUGS AND DRUG RESISTANCE IN TOXPLASMOSIS

弓形虫病中的抗球虫药和耐药性

基本信息

批准号：
3139461
负责人：
ELMER R PFEFFERKORN
金额：
$ 18.8万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-09-30 至 1993-04-30
项目状态：
已结题

项目摘要

Toxoplasmic encephalitis is a common opportunistic infection in AIDS patients. The currently available chemotherapy with pyrimethamine plus a sulfa drug does not always prevent death. Thus new drugs are needed to treat toxoplasmosis in immunosuppressed patients. These new drugs will be sought among the many anticoccidial agents that have been designed to treat infections of chickens with Eimeria species. Two of these anticoccidials, arprinocid and emimycin, have already shown potent activity in animal experiments. Mutants of Toxoplasma gondii resistant to both these drugs have been isolated. One mutant has been used to prove that the form of arprinocid that is active in vivo is the N-oxide. The mechanism of action of emimycin and of arprinocid-N-oxide will be determined. Emimycin is likely to affect pyrimidine metabolism in the parasite while arprinocid-N-oxide may affect purine metabolism. The actions of both drugs will be studied initially by analyses of their effects on the nucleotide pool of T. gondii. Among the additional biochemical aspects to be examined will be permeability to the drug, effects of the drug on various purine and pyrimidine salvage enzymes, and incorporation of the drug into nucleic acids. The mechanisms of action of other antitoxoplasma drugs that will be identified by screening a large catalogue of anticoccidials will also be studied. A key component in analyzing these mechanisms will be the use of multi- and single-step drug resistant mutants of T. gondii. In addition, already isolated mutants of the parasite resistant to pyrimethamine will be studied by comparing the wide type and mutant dihydrofolate reductases. Similarly, already isolated mutants, of T gondii resistant to sulfadiazine will be examined by comparing the wild type and mutant guanosine triphosphate cyclophydrolases. Understanding the mechanisms of action of these various drugs should provide valuable insights into the basic biology and biochemistry of this parasite.

弓形虫脑炎是一种常见的机会性感染艾滋病患者。当前可用的化学疗法与嘧啶和硫酸药物并不总是防止死亡。因此，需要新药来治疗毒质剂免疫抑制的患者。这些新药将被寻求在众多设计用于治疗鸡种鸡的感染。其中两个抗胸膜，arprinocid和emimycin已经显示动物实验的有效活性。弓形虫的突变体对这两种药物的抗体具有抗药性。一突变体已被用来证明arprinocid的形式活体体内是N-氧化物。作用机理将确定Emimycin和arprinocid-N-氧化物的。 Emimycin可能会影响嘧啶代谢寄生虫虽然砷酸-N-氧化物可能会影响嘌呤代谢。最初将通过分析来研究两种药物的作用它们对T. gondii的核苷酸池的影响。在需要检查的其他生化方面将是对药物的渗透性，药物对各种嘌呤的影响，嘧啶拯救酶，并将药物掺入核酸。其他抗氧气的作用机制可以通过筛选大型目录来识别的药物还将研究抗癌。分析的关键组成部分这些机制将是使用多和单步药物 T. gondii的抗性突变体。另外，已经孤立了将研究抗嘧啶的寄生虫的突变体通过比较宽类型和突变二氢叶酸还原酶。同样，已经孤立的突变体，抗tgonii的抗性将通过比较野生型和突变的鸟嘌呤三磷酸环磷酸酶。理解这些各种药物的作用机制应提供对此的基本生物学和生物化学的宝贵见解寄生虫。