Reviving extinct antibiotic molecules encoded in the DNA of Neanderthals and Denisovans could provide a new weapon in the fight against antimicrobial resistance.
Last year, at the University of Pennsylvania and his colleagues reported on .
Now, de la Fuente and many of the same researchers have identified six more antibiotic peptides encoded in ancient mitochondrial DNA previously extracted from Neanderthals and Denisovans, but which haven鈥檛 been seen in modern humans.
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鈥淲e鈥檝e always dreamed of bringing back extinct organisms like the dinosaurs, as in Jurassic Park. But of course, that has a lot of ethical, ecological and technical problems,鈥� says de la Fuente. 鈥淚nstead of bringing back entire organisms, we thought, could we bring back molecules from the past, that could help with problems like antibiotic resistance we see today?鈥�
De la Fuente and his colleagues created an AI that simulates how modern versions of human enzymes called proteases would cleave proteins, encoded by ancient DNA, into fragments known as peptides. They ranked 69 ancient peptides that the AI identified based on their predicted antimicrobial activity by assessing molecular properties such as positive or negative charge.
鈥淥ur hypothesis is that when you get infected, there might be proteases that increase or decrease in levels in different areas of the body, and that could cleave proteins to produce fragments that operate as antimicrobials 鈥� essentially serving as part of the immune system,鈥� says de la Fuente.
The researchers then ordered the peptides from a firm that can manufacture them from the relevant DNA sequences. By adding the 69 molecules to Petri dishes containing a range of bacteria, de la Fuente and his colleagues discovered six previously unknown antibiotic ones.
Three of them came from Neanderthals and three from Denisovans, and each worked against at least one species of bacterium. These included Escherichia coli, Pseudomonas aeruginosa 鈥� which causes lung and blood infections in hospitals 鈥� and Acinetobacter baumannii, which infects people with suppressed immune systems.
One of the Neanderthal peptides also worked against methicillin-resistant Staphylococcus aureus, or MRSA, sometimes known as a superbug because it is resistant to several widely used antibiotics.
To see how the ancient antibiotics worked in animals, the researchers tested two of the Denisovan ones against P. aeruginosa skin infections, and a Neanderthal one against A. baumannii skin infections, all in mice. The tested molecules reduced bacterial levels by at least three orders of magnitude and were as effective as a clinically approved antimicrobial peptide called polymyxin B.
Further analysis revealed that the antibiotic molecules punctured the bacterial cell membranes. By having positively charged and water-repellent regions, the molecules can insert themselves into negatively charged membranes of bacterial cells, forming pores that kill the bacteria, says de la Fuente.
The antibiotic peptides have a high chance of being safe in the body, says de la Fuente, although further research is needed to confirm this.
鈥淲e think evolution is a great filter of things that work and things that are going to be safe and effective. By mining from ancient organisms, we probably will have to worry about safety less than designing drugs from scratch,鈥� says de la Fuente.
鈥淕iven the current global mass extinction, this ability to 鈥榙e-extinct鈥� potential antibiotics is hugely important. The antimicrobial peptides are non-toxic, comparably potent to other antimicrobial peptides and had good effectiveness in a mouse model,鈥� says at the University of Bristol, UK.
鈥淣ature has had billions of years to produce an incredible array of antibiotic antimicrobial peptides and small molecules. It would be a shame if they were lost to humanity before we even knew they were there,鈥� says Williams.
Reference: bioRxiv,
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