‘Pharaoh’s Curse’ fungus transformed into anti-cancer drug

By Stephen Beech

The "Pharaoh's Curse" fungus has been transformed into an anti-cancer drug.

Scientists isolated a new class of molecules from Aspergillus flavus, a toxic crop fungus linked to infamous deaths following the excavations of ancient tombs.

After archaeologists opened King Tutankhamun’s tomb in the 1920s, a series of untimely deaths among the excavation team fueled rumors of a "pharaoh’s curse."

Decades later, doctors theorized that fungal spores, dormant for millennia, could have played a role.

A dozen scientists entered the tomb of Casimir IV in Poland In the 1970s but, within weeks, 10 of them died.

Later investigations revealed the tomb contained A. flavus, whose toxins can lead to lung infections, especially in people with compromised immune systems.

Now, that same fungus is the unlikely source of a promising new cancer therapy.

American scientists modified the chemicals they isolated from A. flavus and tested them against leukemia cells.

Their findings, published in the journal Nature Chemical Biology, showed a "promising" cancer-killing compound that rivals already-approved drugs - and opens new frontiers for fungal medicines.

Study senior author Dr. Sherry Gao, of the University of Pennsylvania, said: “Fungi gave us penicillin.

“These results show that many more medicines derived from natural products remain to be found.”

She explained that the therapy in question is a class of ribosomally synthesized and post-translationally modified peptides, or RiPPs.

The name refers to how the compound is produced - by the ribosome, a tiny cellular structure that makes proteins - and the fact that it is modified later to enhance its cancer-killing properties.

Study first author Dr. Qiuyue Nie said: “Purifying these chemicals is difficult."

She says that while thousands of RiPPs have been identified in bacteria, only a handful have been found in fungi.

Dr. Nie said that is because researchers previously misidentified fungal RiPPs as non-ribosomal peptides and had little understanding of how fungi created the molecules.

She added: “The synthesis of these compounds is complicated.

“But that’s also what gives them this remarkable bioactivity.”

To find more fungal RiPPs, the research team first scanned a dozen strains of Aspergillus, which previous research suggested might contain more of the chemicals.

By comparing chemicals produced by these strains with known RiPP building blocks, the researchers identified A. flavus as a "promising" candidate for further study.

Genetic analysis pointed to a particular protein in A. flavus as a source of fungal RiPPs.

When the researchers turned the genes that create that protein off, the chemical markers indicating the presence of RiPPs also disappeared.

They said the new approach - combining metabolic and genetic information - not only pinpointed the source of fungal RiPPs in A. flavus, but could also be used to find more fungal RiPPs in the future.

Further experiments suggested that asperigimycins likely disrupt the process of cell division.

Dr. Gao said: “Cancer cells divide uncontrollably.

“These compounds block the formation of microtubules, which are essential for cell division.”

She says the compounds had little to no effect on breast, liver or lung cancer cells - or a range of bacteria and fungi - suggesting that asperigimycins’ disruptive effects are specific to certain types of cells, a critical feature for any future medication.

As well as showing the medical potential of asperigimycins, the research team also identified similar clusters of genes in other fungi, suggesting that more fungal RiPPS remain to be discovered.

Dr. Nie said: “Even though only a few have been found, almost all of them have strong bioactivity.

“This is an unexplored region with tremendous potential.”

The researchers say the next step is to test asperigimycins in animal models, with the hope of one day moving to human clinical trials.

Dr. Gao added: “Nature has given us this incredible pharmacy.

"“It’s up to us to uncover its secrets.

"As engineers, we’re excited to keep exploring, learning from nature and using that knowledge to design better solutions.”