Triclosan, a once-ubiquitous antimicrobial agent that is now embroiled in controversy, may be effective in treating one of the world’s worst diseases, according to findings from the University of Cambridge.
Each year, millions of people worldwide suffer from malaria infections and nearly 500,000 of those die. Scientists identified the cause of the disease – a mosquito-bourne protozoan – over 100 years ago, and several treatments and preventative medications exist. Yet like many bacteria, the single-celled parasite continues to evolve resistance to our drugs, making the search for next-generation antimalarials a top priority in the public health field.
Nearly 20 years ago, scientists noted that triclosan, already known as a popular antibacterial agent, could slow the growth of the malaria protozoan using the same mechanism it applies to bacteria: Inhibition of a cell membrane building enzyme called ENR.
Researchers then tried to develop triclosan-based compounds with boosted affinity for ENR, but the drugs failed to treat malaria infections because the parasites only crucially rely on this enzyme during the first part of their life cycle, when they hunker down in the liver to begin mass asexual reproduction. The second, or “erythrocytic” phase, begins when the new army of protozoans migrate into the bloodstream, invading and killing red blood cells. It is at this point that the severe, flu-like symptoms of the malaria disease manifest.
It turns out, however, that the triclosan molecule had another trick in its repertoire all along – one that was overlooked until an artificial intelligence "robot scientist" named Eve joined in on the action.
Developed at the University of Manchester, Eve serves to speed up the drug discovery process by rapidly screening huge numbers of compounds to see if they are active against a chosen target, such as a species of bacteria or parasite. It can then “automatically develop and test hypotheses to explain observations, run experiments using laboratory robotics, [and] interpret the results,” according to a statement from Eve’s engineers.
When evaluating the molecular action of triclosan, Eve showed that the compound blocks the activity of an additional malarial enzyme that is essential to the blood phase, called DHFR. Many of the currently available malaria drugs also target DHFR, yet resistance to these agents is growing among several strains of the protozoan.
The group’s paper, published in Scientific Reports, provides evidence from four separate experiments demonstrating that triclosan can block versions of the DHFR enzyme in both resistant and wild-type malaria protozoans.
Establishing that triclosan works against both ENR and DHFR is especially exciting because no existing malaria medications are able to target the parasite during both stages of its lifecycle. To fully eliminate the infection in the blood and liver, patients are put on multidrug cocktails.
"The discovery by our robot 'colleague' Eve that triclosan is effective against malaria targets offers hope that we may be able to use it to develop a new drug," said lead author Dr Elizabeth Bilsland. "We know it is a safe compound, and its ability to target two points in the malaria parasite's lifecycle means the parasite will find it difficult to evolve resistance."
Meanwhile, Eve (and her brother Adam) will continue to help medical researchers pinpoint new therapies for a variety of diseases.