title: The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis.
abstract: 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.
authors.affiliation: Department of Biomolecular Sciences, Institute of Science and Technology, University of Manchester, Sackville Street, Manchester M60 1QD, UK. tpashly@umist.ac.uk
authors.forename: Tanya V
authors.initials: TV
authors.lastname: Aspinall
authors.forename: David H M
authors.initials: DH
authors.lastname: Joynson
authors.forename: Edward
authors.initials: E
authors.lastname: Guy
authors.forename: John E
authors.initials: JE
authors.lastname: Hyde
authors.forename: Paul F G
authors.initials: PF
authors.lastname: Sims
mesh_terms: D000818:Animals; D003049:Coccidiostats / Q000494:pharmacology* / Q000627:therapeutic use; D004094:Dihydropteroate Synthase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014122:Toxoplasma / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D003049:Coccidiostats; D013449:Sulfonamides; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase