New drug targets both drug-sensitive and drug-resistant malaria

Researchers led by teams at the University of California, Riverside (UCR), the University of California, Irvine and the Yale School of Medicine have developed a compound that they say is effective against drug-susceptible and drug-resistant strains of the malaria parasite Plasmodium falciparum in vitro and in a humanized mouse model engineered to contain human blood. The synthetic compound, called MED6-189, is inspired by natural products derived from sea sponges.

Describe their work in Science“A potassium hinol analog disrupts apicoplast function and vesicular transport P. falciparum Malaria,” researchers led by Karine Le Roch, PhD, professor of molecular, cellular and systems biology at UCR, reported that MED6-189 blocked both asexual replication and sexual differentiation P. falciparumand was also effective against it P knowlesi And P. cynomolgi Parasites. In their research article summary, Le Roche and colleagues concluded: “Our results demonstrate that MED6-189 is a multitarget compound with limited ability of the parasite to develop drug resistance, representing a promising new approach in the fight against malaria.”

In 2022, most of the estimated 619,000 global deaths were caused by malaria Plasmodium falciparumthe most virulent, widespread and deadly human malaria parasite, the authors reported. For decades, the parasite's resistance to antimalarial drugs has posed a major challenge for researchers working to stop the disease's spread. “Due to widespread resistance to commonly used antimalarials, artemisinin-based combination therapies (ACTs) represent the last resort in the antimalarial armamentarium,” the team wrote. However, there are also reports of emerging ACT resistance in different regions of the world. “There is therefore an urgent need to find new therapeutics to combat the ever-growing threat of drug resistance and suppress the spread of the disease,” the team continued. “Ideally, such molecules should target pathways that currently approved antimalarial drugs or those in clinical development do not target.”

MED6-189 is a synthetic analogue of the kalihinol family of isocyanoterpene natural products derived from marine sponges that have previously been found to exhibit potent anti-drug susceptibility and drug-resistant activity P. falciparum isolated, investigators found.

For their newly published study, MED6-189 was synthesized in the laboratory of Christopher Vanderwal, a professor of chemistry and pharmaceutical sciences at UC Irvine. The team developed a system to scale up synthesis to support in-depth mechanism of action studies and enable them to investigate toxicology and in vivo efficacy.

Their study results showed that MED6-189 disrupts apicoplast biology, slowing growth and killing the parasite, the team noted in the abstract of their research article. The apicoplast is an organelle essential for the synthesis of parasite fatty acids and isoprenoids, they explained. “Transcriptomic, metabolomic and proteomic experiments showed that the compound not only affects lipid metabolism but also vesicle transport,” the team continued.

The researchers believe that MED6-189's dual mechanism of action – targeting the apicoplast and disrupting vesicular transport pathways – prevents the pathogen from developing resistance, suggesting that the drug is a promising new approach in the fight against malaria could be.

Vanderwal added: “Many of the best antimalarials are or are derived from natural products. For example, artemisinin, originally isolated from the wormwood plant, and analogues thereof are crucial for the treatment of malaria. MED6-189 is a close relative of another class of natural products called isocyanoterpenes, which appear to target multiple metabolic pathways P. falciparum. This is advantageous because if only one signaling pathway were attacked, the parasite could develop resistance to the compound more quickly.”

For their in vivo tests, researchers at GSK in Spain administered MED6-189 to the infected mice P. falciparumThis shows that the mice were freed from the parasite. Working with Choukri Ben Mamoun, PhD, a professor of medicine and microbial pathogenesis at Yale School of Medicine, the team also countertested the compound P. knowlesia parasite that infects monkeys and found that it eliminates the monkey's red blood cells infected with the parasite. The team reported their studies and found that MED6-189 inhibits both drug-sensitive and drug-resistant drugs P. falciparum Tribes. “Phenotypic testing showed that this compound blocked sexual differentiation of parasites, had a promising tolerance profile toward human cells, and was cleared P. falciparum infection in a humanized mouse model,” they wrote. “The compound also showed strong activity against P. knowlesi And P. cynomolgi.

Le Roch added: “Disrupting apicoplast and vesicle transport blocks development of the parasite, thereby eliminating infection in red blood cells and in our humanized mouse model.” P. falciparum Malaria. We found that MED6-189 is also effective against other zoonotic Plasmodium parasites such as: P. knowlesi And P. cynomolgi.”

Next, the team plans to continue optimizing MED6-189 and further confirm the modified compound's mechanisms of action using a systems biology approach, allowing researchers to study how different living organisms and cells interact at larger scales.

“Overall, our results show that MED6-189 has an efficient and sophisticated mechanism of action, against which it has proven difficult for the pathogen to develop resistance,” the authors explained. “These combined properties make MED6-189 an optimal candidate for use in combination with fast-acting compounds or as a preventive measure with less susceptibility to the emergence of drug resistance.”