Pharaoh’s Curse Fungi Becomes a Powerful Cancer Fighter

The deadly fungi that may have killed archaeologists exploring Tut’s tomb have turned into promising leukemia treatments.

Pennsylvania engineers have isolated and modified compounds with Aspergillus flavus, a toxic yellow spore fungus associated with mysterious deaths after the excavation of ancient tombs – creating anti-cancer molecules that rival FDA-approved drugs to destroy leukemia cells.

The study, published in Natural Chemical Biology, represents a huge reversal of microorganisms long considered to be villains. A. Flavus once brought places of death and now offers hope for cancer patients with a new compound called Asperigimycins.

From ancient tombs to modern medicine

Aspergillus Flavus has earned a sinister reputation through a series of archaeological tragedies. After the tomb of King Tutankhamun opened in the 1920s, several team members died in a mysterious environment, fueling the legend of the pharaoh’s curse. Decades later, medical experts theoretically believe that dormant fungal spores awakened thousands of years later may trigger a fatal lung infection.

This pattern was repeated in Poland in the 1970s, and ten of the twelve scientists entering the tomb of Casimir IV died within weeks. Later investigations showed that the grapes in the entire burial room were resistant to pollution.

“Fungi gave us penicillin,” explains Sherry Gao, associate professor of Pennsylvania’s Cedo and senior author of the study. “These results suggest that more drugs derived from natural products are still to be discovered.”

Hunting hidden molecules

The team focuses on ribosome synthesis and post-translationally modified peptides or cracks – these peptides are known to be difficult to find and purify. Although thousands were found in bacteria, only a few exist in fungi, partly because researchers previously mistaken them for different types of compounds.

The researchers screened twelve Aspergillus strains using innovative methods that combine metabolic analysis with genetic information. By comparing these strains with chemicals produced by known RIPP components, they identified A. Flavus as the most promising candidate.

“Purification of these chemicals is difficult,” said first author and postdoctoral researcher Qiuyue Nie. “But that’s what gives them this extraordinary biological activity.”

Engineering assassin

After isolating four different cracks from A. flavus, the team found that they shared a unique Hempt structure—seven interlocking rings formed an unprecedented molecular structure. These violent mycins show immediate anti-cancer potential, and even without modification, two variants show powerful effects on leukemia cells.

The real breakthrough was when researchers added the lipid components found in Royal Jelly, which are the substances that nourish and nourish bees. This modified version (specified as 2-L6) manifests as effectively as Cytarabine and Daunorubicin, two FDA-approved leukemia drugs that have been used for decades.

Main research results

• Modified balamycin can achieve nanomolar efficacy of three leukemia cell lines
• These compounds specifically target cancer cells with minimal impact on healthy tissues
• SLC46A3 transporter controls cellular uptake of modified compounds
• Sperigimycins destroy microtubule formation and prevent cancer cell division
• Similar gene clusters in other fungi propose more therapeutic compounds waiting to be discovered

Cellular gateway discovery

To understand why lipid modifications improve efficacy, the researchers systematically activate and inactivate genes in leukemia cells. They found that SLC46A3 is a transporter, which is a key gateway that enables pyromycin to enter cells in sufficient amounts.

“This gene works like a portal,” Ni explained. “It not only helps highly toxic erythromycin enter cells, but also makes other ‘cyclic peptides’ do the same.” This discovery could benefit nearly twenty cyclic peptides that have been approved for the treatment of cancer, lupus and other diseases, many of which require modification to achieve sufficient cell permeability.

Targeting of Accurate Cancer

Further experiments showed that pyongmycin works by disrupting the formation of microtubulees, thereby blocking the cellular mechanisms required for division. “Cancer cells divide uncontrollably,” Gao Gao noted. “These compounds prevent microtubule formation, which is crucial for cell division.”

Crucially, these compounds have little effect on breast, liver or lung cancer cells and do not harm a variety of bacteria and fungi. This selectivity suggests that antimycin can target specific cancer types while minimizing side effects, a key advantage of any potential drug.

The team also identified similar genetic clusters in other fungal species, suggesting that nature’s pharmacies contain more undiscovered therapeutic compounds. “Even if only a few people have found a few, almost all have strong biological activity,” Ni observed. “This is an unexplored area with great potential.”

As the animal testing program serves as the next step towards potential human trials, this work illustrates how engineering approaches translate ancient threats into modern treatments. As Gao summed up: “Nature has given us this incredible pharmacy. It depends on our secret.”

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