Reviving Molecules: A Promising Approach to Combatting Superbugs
Bioengineers are revolutionizing antibiotic discovery by resurrecting ancient molecules, including from Neanderthals Using AI-based methods, they aim to combat superbugs and pave the way for a new era in medicine
Rediscover the quest for new antibiotics, which is now taking inspiration from the Stone Age.
The need to find potential candidates is now more pressing than ever, with nearly 5 million deaths annually linked to microbial resistance, as reported by the World Health Organization.
Bioengineering pioneer César de la Fuente and his research team are utilizing artificial intelligence-based computational techniques to extract genetic data from extinct human relatives like Neanderthals, as well as ancient ice age creatures such as the woolly mammoth and giant sloth.
The scientists have discovered small protein molecules, called peptides, that have the ability to fight bacteria and could lead to the development of new drugs to combat human infections. This groundbreaking research has also revolutionized the approach to drug discovery, uncovering new types of molecules and expanding the understanding of molecular diversity. According to de la Fuente, this discovery presents an opportunity to target current problematic pathogens with molecules that bacteria have never encountered before.
Experts stress the urgent need for novel approaches to address the critical issue of antimicrobial resistance, which poses a serious threat to global health. Michael Mahan, a professor at the University of California, Santa Barbara, suggests that a comprehensive approach encompassing land, sea, and air may be necessary to tackle this crisis. He also emphasizes the potential value of looking to the past for solutions to inform future strategies.
An image of a Neanderthal man on display at the Natural History Museum in London. Scientists are employing computational techniques based on AI to extract genetic data from prehistoric human relatives like the Neanderthals.
Mike Kemp/In Pictures/Getty Images
Antibiotics and where their alternatives may come from
Most antibiotics are derived from bacteria and fungi and have been found through the screening of microorganisms in soil. However, in recent years, many of these drugs have become ineffective due to the overuse of antibiotics.
Tom Patterson (left) and his wife Steffanie Strathdee (right)
UC San Diego
Unable to find an effective antibiotic, this woman sought a natural solution to save her husband's life - turning to phages, viruses created by nature to combat bacteria. In the ongoing battle against superbugs, scientists are investigating a variety of potential weapons, with phages emerging as a promising alternative.
Research into antimicrobial peptides (AMPs) offers an exciting avenue for the development of infection-fighting molecules. These peptides, produced by a variety of organisms including bacteria, fungi, plants, and animals (including humans), exhibit a broad range of antimicrobial properties against viruses, bacteria, yeast, and fungi, according to Mahan. Unlike traditional antibiotics, which target a single point within a cell, AMPs bind to and disrupt bacterial membranes at multiple locations, creating a more complex mechanism that may reduce the likelihood of drug resistance. However, Mahan notes that because of their potential to disrupt cell membranes, AMPs may also lead to increased toxicity.
Several peptide-based antibiotics are currently used in clinical settings, including colistin, a bacteria-based AMP. It is utilized as a last-resort drug for specific bacterial infections due to its potential toxicity, as explained by Mahan. Furthermore, human AMP LL-37 has displayed promise in research.
Additionally, unexpected sources such as pine needles and the blood of the Komodo dragon have revealed other potentially effective AMPs.
Rewritten
A moment inspired by Jurassic Park
For the past ten years, De la Fuente had been utilizing computational methods to evaluate a variety of peptides as potential antibiotic alternatives. The notion to explore extinct molecules arose during a lab meeting, sparked by a reference to the blockbuster film "Jurassic Park."
The concept in the film was to resurrect entire organisms, which faced numerous challenges," he explained. They then began contemplating a more realistic approach: "What about extracting molecules from the past?"
With advancements in the extraction of ancient DNA from fossils, comprehensive genetic libraries of extinct human relatives and long-forgotten animals are now readily accessible to the public.
The research team utilized an AI algorithm to identify potential antimicrobial peptides in fragmented sites of human proteins. This algorithm was applied to protein sequences of modern humans, Neanderthals, and Denisovans. The scientists then analyzed the properties of these peptides to determine their potential to combat bacteria.
A bioengineering pioneer, César de la Fuente from the University of Pennsylvania, found that out of six promising peptides identified with an algorithm, one from a Neanderthal was the most effective at fighting pathogens in bacteria-infected mice.
Researchers at the University of Pennsylvania, in collaboration with Science Direct, conducted a study where they synthesized and tested 69 promising peptides to determine their ability to kill bacteria in petri dishes. After careful evaluation, the team identified six highly potent peptides - four from Homo sapiens, one from Homo neanderthalensis, and one from Denisovans. These peptides were then administered to mice infected with the bacterium Acinetobacter baumannii, which is known to cause hospital-acquired infections in humans.
De la Fuente described the most thrilling moment as resurrecting molecules in the laboratory through chemistry and bringing them back to life for the first time. He emphasized the importance of this moment from a scientific perspective. The research, published in August in the scientific journal Cell Host & Microbe, showed that in infected mice with skin abscess, the peptides effectively killed the bacteria. In mice with thigh infection, the treatment was less effective but still managed to halt the growth of bacteria.
"The best (peptide) was what we call Neanderthalien 1, which comes from Neanderthals. And that was the one that was most effective in the mouse model," de la Fuente said.
Jean Lee, a PhD student at Melbourne's Doherty Institute, presented the superbug Staphylococcus epidermidis on an agar plate in Melbourne on September 4, 2018. This superbug, resistant to all known antibiotics and capable of causing severe infections or even death, is silently spreading through hospital wards worldwide, according to Australian scientists on September 3. University of Melbourne researchers found three variants of this multidrug-resistant bug in samples from 10 countries, including strains in Europe that are resistant to all currently available drugs. (Photo by William WEST / AFP)(Photo credit should read WILLIAM WEST/AFP via Getty Images)
The UN report highlights that climate change is fueling the emergence of superbugs.
The researcher noted that while the peptides are not yet suitable for use as antibiotics, they will need significant adjustments. He emphasized the significance of the framework and tools created by his team for identifying potential antimicrobial compounds from previous research.
De la Fuente and his colleagues have developed a new deep-learning model to explore the "extinctome," which consists of the protein sequences of 208 extinct organisms with detailed genetic information. Their research, to be published next year, has revealed over 11,000 previously unknown potential antimicrobial peptides unique to extinct organisms. Promising candidates have been synthesized from the Siberian woolly mammoth, Stellers sea cow, the 10-foot-long Darwins ground sloth, and the giant Irish elk. The team found that the peptides they discovered displayed "excellent anti-infective activity" in mice.
"Molecular de-extinction offers a unique opportunity to combat antibiotic resistance by resurrecting and tapping into the power of molecules from the past," he said.
A wacky but worthwhile approach
Dr. Dmitry Ghilarov, a leader of a research group at the John Innes Centre in the United Kingdom specializing in peptide antibiotics, highlighted the main obstacle in discovering new antibiotics: the reluctance of pharmaceutical companies to develop and clinically test potential peptide antibiotics, which can be challenging to synthesize and can be unstable. He was not part of the study.
"I don't currently see a need to focus on paleo proteomes. We already have plenty of these peptides," he stated. "What we truly need, in my opinion, is a deep understanding of the fundamental principles that make a peptide bioactive, in order to design them effectively."
Ghilarov stated that many peptide antibiotics have not been further developed by the industry due to challenges such as toxicity. A paper published in May 2021 revealed that out of 10,000 potential compounds, only one or two antibiotic drugs were approved by the US Food and Drug Administration.
Denise Catacutan, a graduate student in the Department of Biochemistry and Biomedical Science at McMaster University and co-author of the paper.
Matt Clarke/McMaster University
A new antibiotic, discovered with artificial intelligence, may defeat a dangerous superbug
Dr. Monique van Hoek, a professor and associate research director at the School of Systems Biology at George Mason University in Fairfax, Virginia, expressed interest in the concept of molecular de-extinction. She noted that it is unusual for a peptide, whether from an extinct species or a living organism, to directly result in a new antibiotic or drug. Instead, such discoveries typically serve as a foundation for further research, with computational methods used to enhance the peptide's potential as a drug candidate. Dr. van Hoek was not involved in the studies.
Van Hoeks' current research is centered around a synthetic peptide that draws inspiration from a peptide found in the American alligator. This peptide is currently in the preclinical testing phase.
"It's progressing very positively at this stage. This is particularly exciting as many of the peptides I have worked on in the past have failed for various reasons," she commented.
Van Hoek suggested that although it may seem unconventional to explore alligators or extinct humans as potential sources of antibiotics, the severity of the crisis justifies this approach.
De la Fuente concurred, stating, "I believe that we need to consider as many diverse and novel approaches as we can, as this will ultimately improve our chances of success."
"I think we can find a lot of potential useful solutions by looking behind us."
