Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone

Chloroquine has been the mainstay of malaria chemotherapy for the past five decades, but resistance is now widespread. Pyrimethamine or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chl oroquine resistance. Both pyrimethamine and proguanil are dihydrofolate red uctase (DHFR) inhibitors, the proguanil acting primarily through its major metabolite cycloguanil. Resistance to these drugs arises due to specific po int mutations in the dhfr gene. Cross resistance between cycloguanil and py rimethamine is not absolute. It is, therefore, important to investigate mut ation rates in P. falciparum for pyrimethamine and proguanil so that DHFR i nhibitor with less mutation rate is favored in drug combinations. Hence, we have compared mutation rates in P. falciparum genome for pyrimethamine and cycloguanil. Using erythrocytic stages of P. falciparum cultures, progress ively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence. Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil. It enhances the degree of ge nomic polymorphism leading to diversity of natural parasite population whic h in turn is predisposes the parasites for faster selection of resistance t o some other antimalarial drugs.