Pharaoh’s Curse Fungus Becomes Potent Cancer Fighter

The deadly fungus that may have killed archaeologists exploring King Tut’s tomb has been transformed into a promising leukemia treatment.

Penn engineers have isolated and modified compounds from Aspergillus flavus—the toxic yellow-spored fungus linked to mysterious deaths following ancient tomb excavations—creating cancer-fighting molecules that rival FDA-approved drugs in their ability to destroy leukemia cells.

The research, published in Nature Chemical Biology, represents a dramatic reversal of fortune for a microbe long considered a villain. Where A. flavus once brought death, it now offers hope for cancer patients through a new class of compounds called asperigimycins.

From Ancient Tombs to Modern Medicine

Aspergillus flavus earned its sinister reputation through a series of archaeological tragedies. After King Tutankhamun’s tomb opened in the 1920s, several team members died under mysterious circumstances, fueling legends of a pharaoh’s curse. Decades later, medical experts theorized that dormant fungal spores awakening after millennia could have triggered fatal lung infections.

The pattern repeated in 1970s Poland, where ten of twelve scientists who entered Casimir IV’s tomb died within weeks. Later investigations revealed A. flavus contamination throughout the burial chamber.

“Fungi gave us penicillin,” explained Sherry Gao, Presidential Penn Compact Associate Professor and senior author of the study. “These results show that many more medicines derived from natural products remain to be found.”

Hunting Hidden Molecules

The team focused on ribosomally synthesized and post-translationally modified peptides, or RiPPs—complex molecules that are notoriously difficult to find and purify. While thousands have been discovered in bacteria, only a handful exist in fungi, partly because researchers previously misidentified them as different types of compounds.

The researchers screened twelve Aspergillus strains using an innovative approach that combined metabolic analysis with genetic information. By comparing chemicals produced by these strains with known RiPP building blocks, they identified A. flavus as their most promising candidate.

“Purifying these chemicals is difficult,” noted Qiuyue Nie, first author and postdoctoral fellow. “But that’s also what gives them this remarkable bioactivity.”

Engineering Molecular Assassins

After isolating four different RiPPs from A. flavus, the team discovered they shared a unique heptacyclic structure—seven interlocking rings forming an unprecedented molecular architecture. These asperigimycins displayed immediate cancer-fighting potential, with two variants showing strong effects against leukemia cells even without modification.

The real breakthrough came when researchers added a lipid component found in royal jelly—the substance that nourishes developing queen bees. This modified version, designated 2-L6, performed as effectively as cytarabine and daunorubicin, two FDA-approved leukemia drugs used for decades.

Key Research Findings

• Modified asperigimycins achieved nanomolar potency against three leukemia cell lines
• The compounds specifically target cancer cells while showing minimal effects on healthy tissue
• SLC46A3 transporter protein controls cellular uptake of the modified compounds
• Asperigimycins disrupt microtubule formation, blocking cancer cell division
• Similar gene clusters in other fungi suggest more therapeutic compounds await discovery

Cellular Gateway Discovery

To understand why lipid modification enhanced potency, the researchers systematically activated and deactivated genes in leukemia cells. They discovered that SLC46A3, a transporter protein, serves as a critical gateway allowing asperigimycins to enter cells in sufficient quantities.

“This gene acts like a gateway,” Nie explained. “It doesn’t just help asperigimycins get into cells, it may also enable other ‘cyclic peptides’ to do the same.” This finding could benefit the nearly two dozen cyclic peptides already approved for treating cancer, lupus, and other diseases—many of which require modification to achieve adequate cellular penetration.

Precision Cancer Targeting

Further experiments revealed that asperigimycins work by disrupting microtubule formation, essentially jamming the cellular machinery required for division. “Cancer cells divide uncontrollably,” Gao noted. “These compounds block the formation of microtubules, which are essential for cell division.”

Critically, the compounds showed little to no effect on breast, liver, or lung cancer cells, nor did they harm various bacteria and fungi. This selectivity suggests asperigimycins could target specific cancer types while minimizing side effects—a crucial advantage for any potential medication.

The research team also identified similar genetic clusters in other fungal species, indicating that nature’s pharmacy contains many more undiscovered therapeutic compounds. “Even though only a few have been found, almost all of them have strong bioactivity,” Nie observed. “This is an unexplored region with tremendous potential.”

With animal testing planned as the next step toward potential human trials, this work exemplifies how engineering approaches can transform ancient threats into modern cures. As Gao concluded: “Nature has given us this incredible pharmacy. It’s up to us to uncover its secrets.”