The Oliver Group have published a new paper in the journal Scientific Reports.
Next time you clean your teeth, check the ingredients in your toothpaste; the chances are that it will contain triclosan. This compound prevents the build-up of plaque bacteria by inhibiting the action of enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis. Triclosan has also been known for some time to inhibit the growth of the blood-stage of the malaria parasite, Plasmodium. However, attempts to chemically modify triclosan into an anti-malarial drug by optimising its action against ENR showed no correlation with its effect against the blood-stage parasite. Moreover, later work showed that Plasmodium does not need to use ENR in its blood stage, but rather only in its liver stage. This conundrum has now been resolved by Steve Oliver, Bessie Bilsland, Liisa van Vliet and Florian Hollfelder from our Department, and their collaborators, in a paper published in Scientific Reports. By combining artificial intelligence, laboratory automation, and smart assays based on engineered yeast strains, they employed the 'robot scientist' Eve in a high-throughput screen that identified triclosan as a specific inhibitor of an entirely different enzyme of the malaria parasite; dihydrofolate reductase (DHFR). This enzyme is the target of a well-established antimalarial drug, pyrimethamine (Daraprim), to which resistance is now common. Their paper provides four independent lines of evidence confirming that triclosan specifically targets both wild-type and pyrimethamine-resistant Plasmodium DHFRs. This finding of a second target for the antimalarial action of triclosan provides hope that it can be developed into a novel dual-action drug to which the malarial parasite will find it difficult to evolve resistance.
The robot scientist Eve was developed by researchers at the Universities of Cambridge, Aberystwyth and Manchester to automate drug discovery. To see Eve in action, watch the YouTube video below.