Revitalizing shed molecules from extinct kin like Neanderthals and mammoths could offer hope in the battle against resistant bugs, scientists suggest
As per the World Health Organization, with nearly 5 million annual deaths globally due to antibiotic resistance, the urgency to identify potential candidates has never been greater.
A research team led by Bioengineering pioneer Cesar de la Fuente employs AI-driven methods to trace extinct human relatives such as Neanderthals and long-lost Ice Age giants like mammoths (genetic information from elephants and giant deer) using synthetic life forms.
Scientists contemplate that some minuscule protein or peptide molecules they've discovered have antibacterial capabilities that could serve as inspiration for new medicines to combat human infections. This innovative work also opens up a completely novel perspective in drug development.
"It allows us to discover new sequences and types of molecules that haven't been found in organisms before, expanding our understanding of molecular diversity," said de la Fuente, an Assistant Professor at the Presidential Leadership Institute of the University of Pennsylvania's Machine Biology Group. "Today's bacteria have never been exposed to these molecules, potentially offering us a better chance to battle the troublesome microbes of today."
While the concept may appear disconcerting, experts assert that innovative approaches are urgently needed to combat antibiotic resistance, a deadly and pressing problem facing global health.
"We're in the midst of an antibiotic resistance crisis. In my opinion, a multi-pronged approach – land, sea, and air – is required to address the issue, and looking back into the past to find possible solutions for the future could very well be part of that approach." Californian Department of Molecular, Cellular, and Developmental Biology, University of Santa Barbara. He wasn't involved in the study.
Antibiotics and Their Alternatives Originate From
Generally, most antibiotics derive from bacteria and fungi, which are discovered through soil screening. However, overuse has caused many disease-causing microorganisms to become resistant to these drugs.
Scientists engaged in the worldwide fight against superbugs explore various potential weapons, including bacteriophages or naturally occurring viruses that prey on bacteria.
Another intriguing research focus is antimicrobial peptides (AMPs), which are infection-suppressing molecules produced by numerous different organisms, including bacteria, fungi, plants, and animals, including humans. Mahan explained that AMP has a broad spectrum of antimicrobial properties against various pathogens, including viruses, bacteria, fungi, and mold.
He added that while traditional antibiotics primarily affect a single target within the cell, antimicrobial peptides bind at multiple sites on bacterial membranes, which may lead to reduced resistance but also enhanced toxicity.
Some peptide-based antibiotics are already clinically utilized, such as colistin, derived from bacterial AMPs. Mahan stated that it is used as a last resort in treating certain bacterial infections because of its potential toxicity. A human AMP called LL-37 also exhibits promise.
Further promising AMPs were discovered in unexpected places: Cedar Needles and Komodo Dragon Blood.
Jurassic Park Moments
Since a decade, de la Fuente has utilized computational methods to evaluate the potential of various peptides as alternative antibiotics. When the blockbuster film "Jurassic Park" was mentioned, a brainstorming session in the lab resulted in the idea of investigating extinct molecules.
"The idea (in the film) is to resurrect entire organisms, and obviously, they had many problems." said he. "But given our current technological capabilities, the prospect of reviving molecules from the past seemed more practical."
Advances in extracting ancient DNA from fossils mean that a publicly accessible databank of genetic information about extinct human relatives and long-lost animals is now available.
To uncover previously unknown peptides, the team trained an AI algorithm to find fragmentation locations in human proteins that may have antimicrobial activity. After applying these sequences to modern humans (Homo sapiens), Neanderthals (Homo neanderthalensis), and Denisovans (another old human species closely related to Neanderthals), the scientists used the properties of previously described antimicrobial peptides to predict which of their newly found ancient counterparts would most effectively kill bacteria.
Next, the researchers synthesized and tested 69 of the most promising peptides to see if they could kill bacteria in a Petri dish. The team selected six effective compounds – four from humans, one from Neanderthals, and one from Denisovans – and fed them to mice infested with Acinetobacter baumannii, a common bacterial cause of nosocomial infections in humans. Relative to human cases, mice suffer acinecobacter baumannii-associated infections more frequently.
"One of the most exciting moments was using chemistry in the lab to bring Molecules to life and then to bring them back to life for the first time." said De La Fuente about the August release of the study in the journal Cell Host & Microbe.
In Acinetobacter baumannii-infected mice that developed skin abscesses, the peptide actively killed bacteria; in humans with thigh infections, the treatment was less effective but still prevented bacterial growth.
"The best one is what we call Neanderthal 1, from Neanderthals. This is the most effective in mouse models," said de la Fuente.
He warned that no single peptide could be an antibiotic on its own, and numerous optimizations are required. What's important, he said, are the frameworks and tools that his team has developed in the past to identify promising antibacterial molecules. In a study set to be published soon, de la Fuente and his colleagues developed a new deep-learning model to explore what he calls "Extinom" – the protein sequences of 208 extinct organisms, for which comprehensive genetic information is available.
Using this model, the team discovered over 11,000 previously unknown antimicrobial peptides ranging from the Siberian Woolly Mammoth to the Steller Sea Cow, an Arctic sea mammal that went extinct in the 18th century, and a promising peptide candidate, synthesized from the 10-foot (3m) long Mammut.
"The molecular extinction offers a unique opportunity to combat antibiotic resistance by resurrecting and exploiting the power of molecules from the past," said he.
A Strange Yet Rewarding Approach
Dmitry Gilarov, head of the Peptide Antibiotic Research Group at the John Innes Centre in the United Kingdom, said that the real obstacle in seeking new antibiotics is not necessarily the lack of promising compounds, but convincing pharmaceutical companies to invest in and develop potential ones. Peptide antibiotics are unstable and difficult to synthesize. He was not involved in the study.
"I don't really see a direct reason to study ancient proteinomes," said he. "We already have many of these peptides."
"I think what we really need is a deeper understanding of the foundational principles. What makes Peptides biologically active? Understanding those principles allows for Peptide design."
"There are many Peptide antibiotics that were not developed and promoted by the industry due to challenges like toxicity," said Gilarov.
According to an article published in May 2021, only one or two of the 10,000 promising compounds discovered by researchers were granted approval by the US Food and Drug Administration.
Monique Van Hoek, a professor and deputy research director at the School of Systems Biology at George Mason University in Fairfax, Virginia, said that the strange idea of exploring ancient sources of antibiotics might not lead directly to new antibiotics or other medications, but it could provide a starting point. Frequently, finding a new peptide does not result in new Antibiotics or medications directly, but it serves as a starting point for researchers. They can then use computational techniques to explore the peptide's potential as a candidate and optimize it.
Her current research focuses on a synthetic peptide inspired by a naturally occurring peptide found in American alligators. This peptide is currently being pre-clinically tested.
"It's going very well. It's exciting because so many other peptides I've worked on in the past have failed for one reason or another." said she.
While other approaches may seem far-fetched - like looking for new sources at crocodiles or extinct humans - they merit consideration given the crisis's magnitude, said Van Hoek.
De la Fuente agreed. "I think what we need are as many new and diverse approaches as possible, which could increase our chances of success." he said.
"I think if we look behind our backs, we can find many potentially useful solutions."
