Publication: Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase
Issued Date
2015-09-01
Resource Type
ISSN
18736254
0001706X
0001706X
Other identifier(s)
2-s2.0-84930643108
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
Acta Tropica. Vol.149, (2015), 64-69
Suggested Citation
Yuwadee Talawanich, Sumalee Kamchonwongpaisan, Worachart Sirawaraporn, Yongyuth Yuthavong Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase. Acta Tropica. Vol.149, (2015), 64-69. doi:10.1016/j.actatropica.2015.05.011 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/36077
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Use of bacterial surrogates as a tool to explore antimalarial drug interaction: Synergism between inhibitors of malarial dihydrofolate reductase and dihydropteroate synthase
Other Contributor(s)
Abstract
© 2015 Elsevier B.V. Interaction between antimalarial drugs is important in determining the outcome of chemotherapy using 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. Here, we describe the use of 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. At 0.05. μM trimethoprim, sum of fractional inhibitory concentrations, σFIC of pyrimethamine with sulfadoxine, pyrimethamine with sulfathiazole, pyrimethamine with sulfamethoxazole, and pyrimethamine with dapsone are in the range of 0.24-0.41. These results show synergism between inhibitors of the two enzymes even in the absence of folate transport and uptake. This bacterial surrogate system should be useful as a tool for assessing the interactions of drug combinations between the DHFR and DHPS inhibitors.