AI Article Synopsis
- Researchers engineered Saccharomyces cerevisiae (yeast) to mimic parasites in drug screening, addressing their complex nutritional needs.
- Using pyrimethamine and various DHFR enzymes, they tested engineered yeast strains, revealing differential sensitivity to the drug based on the parasite source.
- This method allows for quick identification of new anti-parasitic agents, validating the yeast strains as reliable models for drug discovery.
Article Abstract
Background: The exacting nutritional requirements and complicated life cycles of parasites mean that they are not always amenable to high-throughput drug screening using automated procedures. Therefore, we have engineered the yeast Saccharomyces cerevisiae to act as a surrogate for expressing anti-parasitic targets from a range of biomedically important pathogens, to facilitate the rapid identification of new therapeutic agents.
Methodology/principal Findings: Using pyrimethamine/dihydrofolate reductase (DHFR) as a model parasite drug/drug target system, we explore the potential of engineered yeast strains (expressing DHFR enzymes from Plasmodium falciparum, P. vivax, Homo sapiens, Schistosoma mansoni, Leishmania major, Trypanosoma brucei and T. cruzi) to exhibit appropriate differential sensitivity to pyrimethamine. Here, we demonstrate that yeast strains (lacking the major drug efflux pump, Pdr5p) expressing yeast ((Sc)DFR1), human ((Hs)DHFR), Schistosoma ((Sm)DHFR), and Trypanosoma ((Tb)DHFR and (Tc)DHFR) DHFRs are insensitive to pyrimethamine treatment, whereas yeast strains producing Plasmodium ((Pf)DHFR and (Pv)DHFR) DHFRs are hypersensitive. Reassuringly, yeast strains expressing field-verified, drug-resistant mutants of P. falciparum DHFR ((Pf)dhfr(51I,59R,108N)) are completely insensitive to pyrimethamine, further validating our approach to drug screening. We further show the versatility of the approach by replacing yeast essential genes with other potential drug targets, namely phosphoglycerate kinases (PGKs) and N-myristoyl transferases (NMTs).
Conclusions/significance: We have generated a number of yeast strains that can be successfully harnessed for the rapid and selective identification of urgently needed anti-parasitic agents.
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|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186757 | PMC |
| http://dx.doi.org/10.1371/journal.pntd.0001320 | DOI Listing |
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