Resistance to antimicrobials is one of the greatest threats that humanity is confronted, which makes the need for new antibiotics more critical than ever. While most antibiotics come from bacteria and fungi, archaea offer a largely unexploited reservoir for the discovery of antibiotics. In a new study, researchers at the University of Pennsylvania took advantage of learning in depth to systematically explore Archéean organizations; By using 233 archaean species proteome, they identified 12,623 molecules with potential antimicrobial activity.
Torre and al. Synthesized 80 archaeasins, 93% of which showed antimicrobial activity in vitro against Acinetobacter baumannii,, They showed cold,, Klebsiella pneumoniae,, Pseudomonas aeruginosa,, Staphylococcus aureus And Enterococcus SPP. Image credit: Torres and al., Two: 10.1038 / S41564-025-02061-0.
“The previous efforts to find new antibiotics have been mainly examined on fungi, bacteria and animals,” said Dr César de la Fuente, researcher at the University of Pennsylvania.
“In the past, we have used AI models to identify antibiotic candidates in a range of improbable sources, DNA of organisms extinguished to the chemicals of animal venom.”
“Now we apply these tools to a new data set: proteins of hundreds of old microbes.”
“There is a completely different field of life waiting to be explored.”
Say separate from bacteria and eukaryotes (which include plants, animals and mushrooms), archaea occupy their own branch on the tree of life.
Although they look like bacteria under the microscope, archaea differ fundamentally in their genetics, their cell membranes and their biochemistry.
These differences allow them to survive in some of the most extreme environments of the earth, from under -stews overheated at hot sources like those of Yellowstone National Park.
Because archaea often thrives where few other organisms can – sustainable overwhelming pressures, toxic chemicals and extreme temperatures – their biology has evolved in an unusual manner.
This makes it a promising but largely unexploited source of new molecular tools, including compounds which can work as antibiotics but which work differently from those currently used.
“We were attracted to the archaea because they had to change the biochemical defenses in unusual environments,” said Dr. Marcelo Torres, also from the University of Pennsylvania.
“We thought that, if they survived for billions of years under these conditions, they may have developed unique ways to fight microbial competitors, and perhaps we could learn.”
To discover potential antibiotic compounds hidden in archaea, the researchers turned to artificial intelligence.
They have exploited an update version of Apex, an AI tool that they originally developed to identify antibiotic candidates in ancient biology, including in the proteins of animals extinct such as woolly mammoth.
After seeing thousands of peptides – short amino acid channels – with known antimicrobial properties, the APEX can predict the probability that a given sequence of amino acids will have similar effects.
By recycling APEX 1.1 on thousands of additional peptides and information on bacteria that cause diseases in humans, scientists have prepared the tool to predict which peptides in archaea could inhibit bacterial growth.
Scanning 233 archaean species gave more than 12,000 antibiotic candidates.
The authors nicknamed these archaeasin molecules, which revealed a chemical analysis differ from known antimicrobial peptides (AMP), in particular in their distribution of electrical load.
They then selected 80 archaeasins to test against real bacteria.
“Trying to find new antibiotics a molecule at a time, it’s like looking for needles in a hay boot,” explains Fangping Wan, a postdoctoral researcher at the University of Pennsylvania.
“AI accelerates the process by identifying where the needles are likely to be.”
Antibiotics work in several ways. Certain punchs in bacterial membranes, while others have closed the ability of organisms to make proteins.
The researchers found that, unlike most of the known amps, which attack the external defenses of a bacteria, the archaeasins seem to pull the cap from the inside, blurring the electrical signals which keep the cell alive.
In tests against a range of bacteria resistant to diseases and drug resistant, 93% of the 80 archaeasins studied have demonstrated an antimicrobial activity against at least one bacteria.
The team then selected three archaeasins to test in animal models.
Four days after a single dose, archaeasins all stopped the spread of a bacteria resistant to medication often acquired in hospitals.
One of the three compounds has demonstrated an activity comparable to polymyxin B, an antibiotic commonly used as the final line of defense against drug resistant infections.
“This research shows that there are potentially many antibiotics that are waiting to be discovered in Archaea,” said Dr. de la Fuente.
“With more and more bacteria developing existing antibiotic resistance, it is essential to find new antibiotics in unconventional places to replace them.”
An article on results has been published today in the journal Nature microbiology.
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Mdt Torres and al. Deep Learning reveals antibiotics in the archaeal proteo. Nat Microbiolpublished online on August 12, 2025; DOI: 10.1038 / S41564-025-02061-0
