Researchers have turned a deadly tomb fungus into a potent cancer-fighting compound. By isolating a new class of molecules from Aspergillus flavus, a toxic crop fungus long linked to the “pharaoh’s curse”, Penn-led scientists have engineered chemicals that kill leukemia cells as effectively as FDA-approved drugs.
“Fungi gave us penicillin,” says Sherry Gao, senior author of the study, published in Nature Chemical Biology.
Aspergillus flavus, named for its yellow spores, haunted archaeological lore after King Tutankhamun’s tomb was opened in the 1920s. A spate of deaths among the excavation team fueled rumors of a curse and later prompted doctors to suspect dormant fungal toxins as the culprit.
In the 1970s, a dozen scientists explored the tomb of Casimir IV in Poland. Within weeks, ten had succumbed to severe lung infections traced back to A. flavus spores.
Now, that same fungus is the unlikely source of a new class of ribosomally synthesized and post-translationally modified peptides, or RiPPs—molecules born at the ribosome and chemically refined to enhance their bioactivity.
“Purifying these chemicals is difficult,” says Qiuyue Nie, the paper’s first author.
The researchers screened twelve Aspergillus strains, comparing their chemical profiles with known RiPP building blocks. Aspergillus flavus emerged as a treasure trove of RiPP precursors.
Genetic analysis pinpointed a specific fungal protein responsible for RiPP production. When the team deleted the gene encoding that protein, the chemical markers for RiPPs vanished—validating a powerful metabolic-genetic strategy for uncovering hidden fungal compounds.
After purifying four distinct RiPPs, the scientists discovered they share a unique architecture of interlocking rings. They dubbed the new molecules asperigimycins, honoring their fungal origin.
Even unmodified, two asperigimycins variants exhibited potent activity against leukemia cells in vitro. A third variant was engineered by attaching a lipid moiety—similar to a fatty component found in royal jelly—which boosted cell-entry and cytotoxicity.
Another variant, to which the researchers added a lipid, performed as well as cytarabine and daunorubicin, two FDA-approved drugs that have been used for decades to treat leukemia.
To unravel the lipid effect, the team manipulated leukemia cell genes one by one. They identified SLC46A3—a gene that helps shuttle compounds out of lysosomes—as critical for allowing cyclic peptides to accumulate inside cells.
“This gene acts like a gateway,” says Nie.
Functional assays revealed that asperigimycins disrupt microtubule formation, blocking the machinery essential for cell division. Remarkably, the compounds showed little to no effect on breast, liver, or lung cancer cells—or on a spectrum of bacteria and fungi—highlighting their targeted action.
In addition to demonstrating the medical potential of asperigimycins, the researchers identified similar gene clusters in other fungi, suggesting that countless RiPPs await discovery.
“Even though only a few have been found, almost all of them have strong bioactivity. Nature has given us this incredible pharmacy. It’s up to us to uncover its secrets,” says Nie.
