U-M team coaxes bacteria to produce a long-elusive compound—opening a new front against drug-resistant malaria
By Emily Kagey
Life Sciences Institute
Bacteria are churning out a potential new treatment for malaria that has remained elusive for over a decade, thanks to genetic engineering and chemical modifications conducted by a team of scientists in the University of Michigan Life Sciences Institute.
Malaria presents a global health crisis, with more than 280 million cases in 2024 and over 600,000 deaths from the infection, the majority in children under the age of five. While antimalarial drugs are available, the parasites that cause the infection continue to evolve new ways to survive the treatments, and multi-drug resistance is on the rise across multiple continents.
“The problem with any fast-replicating organism, like this parasite, is that it can develop resistance to current drug regimens if they are used over extended periods of time,” says David Sherman, a faculty member at the LSI, College of Pharmacy, Medical School and College of Literature, Science, and the Arts. “So it is imperative that we continue urgent efforts to stay a step ahead of the parasite.”
About 10 years ago, scientists discovered bacteria producing small quantities of a chemical compound called premarineosin A, which showed strong anti-malarial properties. Further research into the compound and its potential as a therapeutic has been hampered, however, by a lack of supply.
“As a research community, we never had enough of this molecule in hand to be able to screen for the best methods to actually modify it,” explains U-M bioengineer Filipa Pereira, a research scientist at the LSI. “Under normal growth conditions in the lab, the bacteria barely produce it. And no one has really found a way to make it efficiently through total chemical synthesis.”
Sherman and Pereira recently teamed up to overcome these challenges. Sherman’s lab at the LSI studies how terrestrial and marine microorganisms produce chemical compounds with important biological activity, and how those natural pathways can be harnessed to develop potential therapeutics. While working with a bacterial strain that Sherman’s lab investigates for its anti-HIV properties, the researchers noticed it also had the genetic blueprints to make premarineosin A.
Pereira specializes in engineering bacterial genomes to coax the microorganisms to make larger quantities and modified versions of the compounds they produce naturally. She found a way to augment a gene that serves as the “on” switch for the genetic pathway that builds premarineosin, resulting in a 150-fold increase in production.
With workable quantities of the compound in hand, the team has begun developing new versions by introducing specific edits to its chemical structure. One compound they developed was over 20 times more active against a drug-resistant strain of the malaria-causing parasite than the starting compound and showed almost no toxicity to human cell cultures: The dosage needed to harm human cell lines is nearly 800 times the dosage that kills the parasite in cell culture.
More research is needed to determine whether the compound can be developed into a safe malaria treatment for humans, and the team is still testing different configurations to find the optimal combination that maximizes the antimalarial effects without causing harm to human cells. But they are optimistic about the new leads this compound opens for developing novel treatments for drug-resistant malaria.
“A lot of the natural products in this premarineosin family have antimalarial, anti-cancer, or antibacterial activities, so there is a lot of potential to explore now that we have a better understanding of how to make and modify this compound,” Pereira said. “But this one in particular shows very low toxicity for human cells, so it has great promise.”