Behind the deaths of the archaeologists who opened the cursed tomb of the Egyptian king Tutankhamun back in 1922, there was a scientific explanation: a fungus, the Aspergillus flavus. These microorganisms had been dormant for millennia, and their toxic spores ended up in the bodies of the expedition members.
But this microbe also hides a new class of molecules to eliminate cancerous blood cells. "Fungi gave us penicillin," says Sherry Gao, associate professor at the University of Pennsylvania in Chemical and Biomolecular Engineering and Bioengineering. Her team has isolated and modified ingredients from a compound derived from the Aspergillus flavus fungus and successfully tested them against leukemia cells.
The findings of this discovery, published this week in Nature Chemical Biology, open the door to the utility of fungal medications. In this case, an anticancer compound that rivals drugs already approved by regulatory agencies against blood tumors.
After its prominence in the Egyptian chapters, this fungus was also linked to the deaths of ten out of twelve scientists who entered the tomb of the Polish king Casimir IV in the 1970s. Subsequent investigations revealed that the tomb contained A. flavus, whose toxins can cause lung infections, especially in individuals with weakened immune systems.
Gao, the lead author of the study, explains to EL MUNDO why she is interested in this toxic fungus. "Despite its reputation for producing toxic aflatoxins, its genome contains unexplored biosynthetic gene clusters. One of these clusters seemed capable of producing a new class of RiPPs [ribosome-inactivating proteins], extremely rare in fungi. This made it a scientific challenge and, at the same time, an opportunity to discover something novel."
However, that compound was not complete, so they needed to modify it. "The original fungal peptides had interesting structures but limited activity," she clarifies. Therefore, they used a kind of lipid tag, "which improved their ability to enter cells." In this way, Gao points out that they obtained a target and an administration mechanism: "The modified compound appears to be more effective against leukemia cells because they could express higher levels of the transporter SLC46A3, which is how our lipid-tagged compounds could hijack the transporter to enter the cell." The scientist argues that this is what makes it especially effective against leukemia.
While one face of the Aspergillus flavus fungus "is its production of aflatoxins, dangerous for humans and animals," the other face consists of many other diverse natural compounds. Among them, the aspergimicins stand out, "a set of heptacyclic peptides. Through chemical enhancement, their modification showed strong anticancer effects by disrupting microtubules and cell division in leukemia cells," explains the biochemist.
This process is not without risks. Gao explains that there were strict laboratory safety protocols due to its production of aflatoxins. "We used strains and conditions that minimized the risk of toxins, and all handling was done in biosafety cabinets." Although she highlights that "the real challenge was not the danger but isolating the RiPPs, present in very low and structurally complex quantities."
With this first step, the University of Pennsylvania team highlights the potential hidden in fungi. "Fungal RiPPs have been little explored compared to bacterial ones. Their structural complexity and specificity make them promising candidates for all kinds of treatments, from anticancer agents to antibiotics or immunomodulators."
Fungi are full of genetic "dark matter" and biosynthetic pathways that have not been characterized, emphasizes the biochemist, and with new tools like genome mining and synthetic biology, "we can now access that hidden chemistry." "This study is just an example of how fungi could transform the future of medicine," concludes Gao.