Archaea, the least understood microbial branch on the tree of life, are emerging as important clues for researching new antibiotics, according to two reports published this week. Famous for their ability to thrive in extreme environments such as hot springs and salt flats, archaea also coexist with bacteria in various habitats. Now, two research teams believe this close relationship may have driven hundreds of archaea to evolve unique chemical defense mechanisms, some of which can kill pathogenic bacteria resistant to traditional antibiotics. While these archaeal compounds have not yet been proven to be directly usable as drugs, the results emphasize that such microbes are promising treasure troves for antibiotic development.
Artificial intelligence screening has identified potential antibiotics in archaea, including species living in hot springs in Yellowstone National Park. (Image source: Peter Adams/Avalon/Universal Images Group via Getty Images)
The related studies are published in Nature Microbiology and PLOS Biology. Jim Collins, a bioengineer at the Massachusetts Institute of Technology focusing on antibiotic discovery, said, "We have neglected archaea research in the past." Archaea lack the outer cell wall found in bacteria and do not have the distinct nucleus and membrane-bound organelles of eukaryotes. Based on these genetic and biochemical differences from bacteria and eukaryotes, archaea—once considered bacteria—are now recognized as a separate domain. However, archaea, bacteria, and single-celled eukaryotes coexist in many environments: for example, archaea participate in methane production in the human digestive tract and assist in wood decomposition in the hindgut of termites. Tobias Warnecke, a biochemist at the University of Oxford in the UK, noted, "If they share an ecological niche, they shouldn’t coexist harmoniously."
To explore whether potential conflicts drive archaea to produce antibiotics, researchers led by Cesar de la Fuente, a biomolecular engineer at the University of Pennsylvania, trained an artificial intelligence (AI) algorithm to scan archaeal proteomes—the complete amino acid sequences of all proteins in an organism. They searched for cryptic peptides with antimicrobial properties, which are protein fragments usually produced by the breakdown of large proteins. Ultimately, in the 233 archaeal proteomes scanned, they identified over 12,600 potential cryptic peptides.
The research team further synthesized 80 of the most promising peptides. Results showed that 93% of these peptides exhibited antimicrobial activity against dangerous human pathogens such as Staphylococcus aureus and Klebsiella pneumoniae in vitro. Further in vitro studies indicated that most of these antimicrobial peptides kill bacteria by depolarizing the bacterial inner cytoplasmic membrane—a strategy distinct from common antimicrobial peptides that destroy the outer cell membrane.
In another study published today in PLOS Biology, Warnecke and his colleagues investigated archaeal antimicrobial effects from a different angle. Unlike archaea, bacteria are surrounded by a mesh-like wall of polymerized peptides called peptidoglycan outside their cytoplasmic membrane. Thus, they wanted to explore whether archaea contain hydrolytic enzymes that can degrade peptidoglycan to protect themselves from bacterial invasion. In fact, the team found such enzymes in 5% of the over 3,700 archaea they surveyed. Protein structure analysis showed that many of these enzymes are secreted extracellularly, and Warnecke’s team even discovered that some archaea possess syringe-like molecular injectors to deliver proteins into bacteria. In laboratory tests, some of these hydrolytic enzymes disrupted bacterial peptidoglycan and killed the bacteria.
Both Warnecke and de la Fuente emphasize that the newly discovered enzymes and peptides are still far from being clinical drugs. However, they agree that more antibiotic resources in archaea remain to be discovered. Warnecke concluded, "This is probably just the tip of the iceberg."