The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis

被引:77
作者
Aspinall, TV
Joynson, DHM
Guy, E
Hyde, JE
Sims, PFG
机构
[1] Univ Manchester, Inst Sci & Technol, Dept Biomol Sci, Manchester M60 1QD, Lancs, England
[2] Publ Hlth Lab, Toxoplasma Reference Unit, Swansea, W Glam, Wales
基金
英国惠康基金;
关键词
D O I
10.1086/340577
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页码:1637 / 1643
页数:7
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