The molecular basis of sulfonamide resistance in Toxoplasma gondii and implications for the clinical management of toxoplasmosis.
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.
Aspinall
Tanya V
TV
Department of Biomolecular Sciences, Institute of Science and Technology, University of Manchester, Sackville Street, Manchester M60 1QD, UK. tpashly@umist.ac.uk
Joynson
David H M
DH
Guy
Edward
E
Hyde
John E
JE
Sims
Paul F G
PF
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
D003049:Coccidiostats; D013449:Sulfonamides; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase