With continuing global threat of malaria, there is an urgent need to search not only for new drugs, but also for effective drug combinations. Inhibitors of dihydrofolate reductase (DHFR) such as pyrimethamine and of dihydropteroate synthase (DHPS) such as sulfa drugs are known to have synergistic interactions. However, studies of the synergism are complicated by the fact that the malaria parasite can also salvage exogenous folates, and the salvage may also be affected by the drugs. It is desirable to have a convenient system to study interaction of DHFR and DHPS inhibitors without such complications.
Researchers used Escherichia coli transformed with malarial DHFR and DHPS, while its own corresponding genes have been inactivated by optimal concentration of trimethoprim and genetic knockout, respectively, to study the interaction of the inhibitors. Marked synergistic effects are observed for all combinations of pyrimethamine and sulfa inhibitors in the presence of trimethoprim. The results show synergism between inhibitors of the two enzymes even in the absence of folate transport and uptake. This bacterial surrogate system can, therefore, be used as a tool for assessing the interactions of drug combinations between the DHFR and DHPS inhibitors.
This study was conducted by researchers from Mahidol University and BIOTEC Protein-Ligand Engineering and Molecular Biology Laboratory.
Full article can be accessed here.
Ref: Talawanich, Y., Kamchonwongpaisan, S., Sirawaraporn, W. and Yuthavong, Y. (2015). Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase. Acta Tropica. 149, 64-69.
Posted on 31 August 2015