Trifluoromethionine, a Prodrug Designed against Methionine γ-Lyase-Containing Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis
Trifluoromethionine, a Prodrug Designed against Methionine γ-Lyase-Containing Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis
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DOI：
10.1128/aac.45.6.1743-1745.2001
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发表时间：
2001-06
影响因子：
4.9
通讯作者：
G. H. Coombs;J. Mottram
中科院分区：
文献类型：
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作者：
G. H. Coombs;J. Mottram
蛋氨酸γ-裂解酶是一种催化蛋氨酸一步转化为α-酮丁酸盐、氨和甲硫醇的酶，在许多厌氧病原微生物中具有高活性，但在哺乳动物中没有相应的酶。本研究验证了一个假设，即这种病原体特异性酶可以被它完全激活的前药用作药物靶标。三氟甲硫氨酸被证实是一种前药，并在体外对厌氧原生动物阴道毛单胞菌、含蛋氨酸γ-裂解酶的厌氧细菌和表达毛滴虫基因的大肠杆菌具有高毒性。该化合物对体内生长的寄生虫也有特殊的活性，单次剂量可以防止六只小鼠中的五只形成病变。这些发现表明，三氟甲硫氨酸是一类新型抗感染药物的先导化合物，具有作为化疗药物治疗一系列原核和真核厌氧病原体的潜力。
ABSTRACT Methionine γ-lyase, the enzyme which catalyzes the single-step conversion of methionine to α-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasiteTrichomonas vaginalis, to anaerobic bacteria containing methionine γ-lyase, and to Escherichia coli expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.