For decades, the proteasome has been considered a simple molecular shredder. It chews up used or damaged proteins and feeds them to T cells to help them scan for danger. However, a new study suggests this cellular machinery harbors a second, secret talent: it might also produce antibiotics that kill bacteria directly.
A team led by researchers from the Weizmann Institute of Science described a surprising twist in the proteasome’s activity. The study reveals that the proteasome can generate “defense peptides” — fragments of proteins that act like antibiotics from within, rupturing bacterial membranes and halting infections before the immune system’s more complex operations even begin.
A Surprise From Within
The proteasome is a microscopic barrel-shaped machine found in every cell of the human body. For decades, scientists only knew it for breaking down old or damaged proteins into fragments so their building blocks could be reused. Immunologist Yifat Merbl and her team suspected the proteasome might be doing more.
In a series of intricate experiments—what she described as “dumpster diving”—they uncovered that the proteasome isn’t just disposing of old proteins. It’s transforming them into molecular weapons. When a cell is infected by bacteria, the proteasome undergoes a key transformation. Rather than just chopping up proteins for recycling, it creates antimicrobial peptides (small fragments capable of tearing holes in the bacterial cell walls) from them.
Under a microscope, the results are stark. Images shared by the team show once-healthy Staphylococcus bacteria ruptured and leaking their contents after exposure to these natural antibiotics.
Field Test Results
To test their theory, the researchers inhibited the proteasome in human cells and then exposed them to Salmonella. Bacterial levels surged. But when the proteasome was allowed to function normally, the cells secreted small peptides that stunted bacterial growth. The effect vanished when these peptides were digested by a general protease, confirming their antimicrobial role.
Digging deeper, the team used a mass spectrometry technique called MAPP (Mass-spectrometry Analysis of Proteasome Products) to catch the peptides in the act. Out of over 50,000 identified peptides, more than 1,000 had the right size and chemistry to be potent antimicrobials.
Ten of the highest-scoring candidates were synthesized and tested against a rogues’ gallery of bacteria — E. coli, Pseudomonas aeruginosa, Micrococcus luteus, and others. Most were vulnerable to the new peptides, which worked in a dose-dependent fashion. The peptides showed no toxic effects on mammalian cells.
One standout was a peptide derived from PPP1CB, a protein involved in phosphatase regulation. Not only did it kill bacteria in lab dishes, but it also reduced bacterial load in infected mice and even boosted survival rates in a mouse model of sepsis when compared to standard antibiotic treatment.
A New Approach in the Antibiotics Crisis
To fully appreciate the significance of this discovery, it’s important to consider the global antibiotic crisis we’re currently in.
Antimicrobial resistance (AMR) is one of the most pressing health challenges of the 21st century. As bacteria evolve to resist the drugs we use against them, infections that were once easily treated—urinary tract infections, pneumonia, sepsis—become deadlier.
In the UK alone, AMR is directly responsible for 7,600 deaths each year and contributes to more than 35,000, according to a recent National Audit Office report. Globally, the figure is over a million deaths annually, and climbing.
Yet the pipeline for new antibiotics has been drying up. Traditional sources—soil microbes and synthetic chemistry—have not kept pace with the growing resistance. That’s what makes the discovery so compelling: it could offer a new way to fight infections.
The fact that these antimicrobial peptides originate from our own cells also offers a potential safety advantage. Drugs derived from them might be less likely to trigger harmful immune reactions, streamlining their development.
“What’s really exciting about this is it’s a totally undiscovered process by which anti-germ molecules are made inside our cells,” said Professor Daniel Davis, an immunologist at Imperial College London. “It feels profoundly important and surprising.”
But he also urged patience. This new source of antibiotics still needs to be tested and that will take time. It might be a breakthrough, but it’s not a usable solution just yet.
If these peptides can be harnessed and refined, they may one day provide a powerful new defense — not just as drugs, but as an entirely new concept of self-made immunity.
The findings were published in Nature on March 27.
