Penn-led researchers have achieved a remarkable scientific breakthrough by transforming Aspergillus flavus, a deadly fungus historically linked to mysterious deaths in ancient tomb excavations, into a source of potent anti-cancer compounds. The research team, led by Sherry Gao, Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering, has isolated and modified a new class of molecules that rival FDA-approved leukemia drugs in effectiveness.
The study, published in Nature Chemical Biology, represents a significant advance in natural product drug discovery, demonstrating how modern biotechnology can unlock therapeutic potential from unlikely sources.
From Ancient Curse to Modern Cure
Aspergillus flavus has long been considered a microbial villain. The yellow-spored fungus gained notoriety after archaeologists opened King Tutankhamun's tomb in the 1920s, when a series of untimely deaths among the excavation team fueled rumors of a pharaoh's curse. Decades later, medical experts theorized that fungal spores, dormant for millennia, could have contributed to these deaths.
The fungus's deadly reputation was further cemented in the 1970s when a dozen scientists entered the tomb of Casimir IV in Poland. Within weeks, 10 of them died, and later investigations revealed the tomb contained A. flavus, whose toxins can cause fatal lung infections, particularly in immunocompromised individuals.
Discovery of Fungal RiPPs
The therapeutic breakthrough centers on a rare class of compounds called ribosomally synthesized and post-translationally modified peptides, or RiPPs. These molecules are produced by cellular ribosomes and subsequently modified to enhance their biological activity.
"Purifying these chemicals is difficult," explains Qiuyue Nie, a postdoctoral fellow in Chemical and Biomolecular Engineering and the paper's first author. While thousands of RiPPs have been identified in bacteria, only a handful have been found in fungi, partly because past researchers misidentified fungal RiPPs as non-ribosomal peptides.
The research team employed an innovative approach, combining metabolic and genetic analysis to identify A. flavus as a promising source of fungal RiPPs. By comparing chemicals produced by various Aspergillus strains with known RiPP building blocks, they pinpointed specific proteins responsible for RiPP production.
Asperigimycins: A New Class of Anti-Cancer Compounds
After purifying four different RiPPs from A. flavus, the researchers discovered that these molecules shared a unique structure of interlocking rings. They named these previously undescribed compounds "asperigimycins" after their fungal source.
The asperigimycins demonstrated remarkable anti-cancer potential in laboratory tests. Two of the four variants showed potent effects against leukemia cells without any modification. Most significantly, when researchers added a lipid component found in royal jelly—the nutrient-rich substance that nourishes developing bees—one variant performed as well as cytarabine and daunorubicin, two FDA-approved drugs used for decades to treat leukemia.
Mechanism of Action and Cellular Entry
The research revealed that asperigimycins work by disrupting microtubule formation, which is essential for cell division. "Cancer cells divide uncontrollably," notes Gao. "These compounds block the formation of microtubules, which are essential for cell division."
Importantly, the compounds showed remarkable specificity, having little to no effect on breast, liver, or lung cancer cells, or on various bacteria and fungi. This selectivity suggests that asperigimycins' effects are specific to certain cell types—a critical feature for any future medication.
The team also identified a crucial mechanism for cellular uptake. Through selective gene manipulation in leukemia cells, they discovered that the SLC46A3 gene plays a critical role in allowing asperigimycins to enter cells in sufficient quantities. This gene helps materials exit lysosomes, the cellular compartments that collect foreign materials.
"This gene acts like a gateway," says Nie. "It doesn't just help asperigimycins get into cells, it may also enable other 'cyclic peptides' to do the same." This discovery provides valuable insights for drug development, as nearly two dozen cyclic peptides have received clinical approval since 2000 to treat diseases ranging from cancer to lupus.
Broader Implications for Drug Discovery
The research has implications beyond A. flavus. The team identified similar gene clusters in other fungi, suggesting that more fungal RiPPs remain to be discovered. "Even though only a few have been found, almost all of them have strong bioactivity," observes Nie. "This is an unexplored region with tremendous potential."
The findings also advance understanding of how lipid modifications can enhance drug delivery. "Knowing that lipids can affect how this gene transports chemicals into cells gives us another tool for drug development," explains Nie.
Next Steps and Future Directions
The next phase involves testing asperigimycins in animal models, with the ultimate goal of advancing to human clinical trials. The research team has filed a provisional patent application to protect their novel chemical discoveries.
"Fungi gave us penicillin," reflects Gao. "These results show that many more medicines derived from natural products remain to be found. Nature has given us this incredible pharmacy. It's up to us to uncover its secrets."
The collaborative research involved institutions including the University of Pennsylvania School of Engineering and Applied Science, Rice University, the University of Pittsburgh, MD Anderson Cancer Center, Washington University School of Medicine, Baylor College of Medicine, and the University of Porto. The study received support from the National Institutes of Health, the Welch Foundation, the Cancer Prevention and Research Institute of Texas, and the National Science Foundation.
