Researchers have identified a previously unknown class of molecules produced by a toxic fungus that has been linked to deaths in ancient tomb excavations. Their findings, published today in Nature Chemical Biology, show that these molecules can have strong anti-cancer activity against leukemia cells, rivaling the effects of drugs currently used to treat this form of cancer.
The new compounds are ribosomally synthesized and post-translationally modified peptides (RiPPs), which englobe a diverse group of peptides with a wide range of biological functions. While RiPPs are known to be a promising source of new therapeutic compounds, most studies to date have focused on RiPPs produced by bacteria. Thousands of RiPPs have been identified in bacteria compared to only a handful in fungi, highlighting that the potential of fungal RiPPs still remains largely unexplored.
“Fungi gave us penicillin,” said Sherry Gao, PhD, associate professor in chemical and biomolecular engineering at the University of Pennsylvania School of Engineering and senior author of the study. “These results show that many more medicines derived from natural products remain to be found.”
The researchers screened 12 strains of Aspergillus fungi and compared the chemicals they produce with known building blocks of RiPPs. This led them to identify Aspergillus flavus as a promising candidate to further study the production of these compounds.
Notably, A. flavus is thought to be responsible for the deaths of several archaeologists over the years, including the team that opened King Tutankhamun’s tomb back in 1922, as spores from this fungus can trigger severe lung infections and are able to lay dormant for millennia.
The researchers isolated four different RiPPs from A. flavus, all based on the same unique chemical scaffold consisting of interlocking rings around a benzofuranoindoline core. As this class of molecules had never been described before, the team named them asperigimycins, after the fungus that produces them.
Without any chemical modifications, two of the four compounds demonstrated potent effects against leukemia cells. As Gao explained, “These compounds block the formation of microtubules, which are essential for cell division.” Importantly, the compounds had little to no activity against breast, liver or lung cancer cells, as well as a range of bacteria and fungi, which suggest they could be promising candidates for highly selective drugs.
The addition of a lipid group to one of the compounds was able to boost its anti-cancer activity, achieving comparable results to cytarabine and daunorubicin, two drugs that have been used to treat leukemia for decades. A genetic analysis revealed that this process was mediated by the SLC46A3 gene, which was key to allowing asperigimycin compounds to enter leukemia cells via lysosomes.
“This gene acts like a gateway,” said Qiuyue Nie, PhD, postdoctoral fellow at the University of Pennsylvania School of Engineering and first author of the study. “It doesn’t just help asperigimycins get into cells, it may also enable other ‘cyclic peptides’ to do the same. Knowing that lipids can affect how this gene transports chemicals into cells gives us another tool for drug development.”
Given the wide reaching potential of these newly described compounds, the researchers also studied the biosynthetic pathways that Aspergillus fungi use to make asperigimycins. This allowed them to identify similar clusters of genes in other fungi, opening the door to discovering many more of these promising molecules.
“The synthesis of these compounds is complicated,” said Nie. “But that’s also what gives them this remarkable bioactivity. Even though only a few have been found, almost all of them have strong bioactivity. This is an unexplored region with tremendous potential.”
As a next step, the research team is planning to test the anti-cancer effects of asperigimycin compounds in animal models, with the goal of eventually entering clinical trials in humans. 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.”
