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Vol. 54, Issue 6, 1140-1147, December 1998
Malaria Genetics Section, Laboratory of Parasitic Diseases,
National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland 20892-0425
The lack of suitable antimalarial agents to replace chloroquine and
pyrimethamine/sulfadoxine threatens efforts to control the spread of
drug-resistant strains of the malaria parasite Plasmodium falciparum. Here we describe a transformation system, involving WR99210 selection of parasites transformed with either wild-type or
methotrexate-resistant human dihydrofolate reductase (DHFR), that has
application for the screening of P. falciparum-specific DHFR inhibitors that are active against drug-resistant parasites. Using
this system, we have found that the prophylactic drug cycloguanil has a
mode of pharmacological action distinct from the activity of its parent
compound proguanil. Complementation assays demonstrate that cycloguanil
acts specifically on P. falciparum DHFR and has no other
significant target. The target of proguanil itself is separate from
DHFR. We propose a strategy of combination chemotherapy incorporating
the use of multiple parasite-specific inhibitors that act at the same
molecular target and thereby maintain, in combination, their
effectiveness against alternative forms of resistance that arise from
different sets of point mutations in the target. This approach could be
combined with traditional forms of combination chemotherapy in which
two or more compounds are used against separate targets.
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