Potent antimalarial compound discovered in natural products collection

JUPITER, Fla. — Scientists hunting for a new malaria treatment may have found a solution within a historic natural compound collection housed at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology.           

Globally, malaria remains one of the most widespread and deadly infectious diseases, sickening an estimated 280 million people annually. It disproportionately kills small children, with about 600,000 deaths every year. Spread through biting mosquitos in tropical areas, malaria parasites are growing resistant to standard therapies such as chloroquine and artemisinin.

“The parasites are evolving, so it’s critically important to identify new antimalarial drugs that have mechanisms of action that differ from past drugs,” said chemist Ben Shen, Ph.D., founder of the Natural Products Discovery Center at The Wertheim UF Scripps Institute. “The compounds we identified originated in soil microbes and extracts housed within our natural products collection.”

The team discovered several compounds capable of rapidly killing the malaria parasite at all stages of its life cycle, unlike existing antimalarial drugs, Shen said.

Co-first author Chantal Bader, Ph.D., a postdoctoral researcher in Shen’s lab, said the team used a systematic process to find the best candidates from a subset of the 122,550-strain  collection, seeking compounds that had not been studied before.

“Bacterial extracts contain thousands of different metabolites. The challenge is to find an active extract, to identify which specific metabolites in these complex mixtures are responsible for the activity, and then to confirm they are truly novel,” Bader said.

The researchers started their quest by screening 81 purified natural compounds selected from the institute’s collection. Their target was a drug-resistant malaria parasite known to cause severe disease. That step revealed six promising candidates from five chemical families.

Then they expanded their screening to 1,531 samples created by 425 microbes, a group of bacteria called Actinobacteria. Of those, they found about 20% had antimalarial properties. Filtering out those toxic to humans, they then studied the top candidates’ chemical composition and activity. That revealed several compounds that had not previously been studied by scientists.

The researchers then cultured the bacteria that produced the novel compounds. They optimized their production, characterized their chemical structures and named them SPAs, short for sphaeriaurantins. The SPAs come from a rare and little-studied group of soil bacteria called Sphaerisporangium, Shen explained. Testing showed the best of the SPAs cleared 99.9% of the multidrug-resistant malaria parasite, Plasmodium falciparum, from blood and cultured liver cells, meaning the compound worked at multiple stages of the parasite’s life cycle. Their testing indicated that the SPAs are unlikely to develop drug resistance.

Their research was published in August in the Journal of the American Chemical Society.

The path from lead discovery to approved medicine can take many years. The researchers’ next steps involve characterizing the pharmacological and therapeutic potential of the SPA scaffold, Shen said. That will require identifying and validating its primary molecular target and understanding the mechanism of action, he said.

The Natural Products Discovery Center at The Wertheim UF Scripps Institute consists of microbes, their extracts and partially purified samples. Shen and his research team have been painstakingly studying the collection to build a genome database for the world’s scientists to search for new natural products.

The collection is irreplaceable, Shen says, noting it was originally amassed by scientists over 80 years, when such collecting was still feasible. International treaties on genetic sovereignty now make such collecting cost prohibitive. Hailing from 77 countries, the collection had been assembled by multiple pharmaceutical companies and research groups specifically for their potential as medicines. Only recently has technology developed to enable rapid sequencing and analysis, and so much of the collection still must be explored.

Natural products have a storied history of providing source material for important medications, dating back to the discovery of penicillin. Two-thirds of drugs approved in the United States originated with or were inspired by natural products, underscoring the value of preserving such biodiversity, Shen said. The collection includes the microbial strains that inspired important medicines such as the antibiotic streptomycin and the immunosuppressant drug rapamycin.

“The Wertheim UF Scripps Institute now houses one of the largest Actinobacteria strain collections in the world,” he said. “We are mining those genetic riches for the benefit of humanity. This discovery of a potent antimalarial is among many potentially useful natural products we have found in this set to date. It is yet more proof of the value of preserving this irreplaceable resource.”