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News — PHILADELPHIA—In a significant advance against the growing threat of antibiotic-resistant bacteria, researchers have identified a novel class of antimicrobial agents known as encrypted peptides, which may expand the immune system’s arsenal of tools to fight infection. , published today in  by Cell Press, reveal that many antimicrobial molecules originate from proteins not traditionally associated with immune responses.

Unlike conventional antibiotics that target specific bacterial processes, these newly-discovered peptides disrupt the protective membranes surrounding bacterial cells. By inserting themselves into these membranes—much like breaching a fortress wall—the peptides destabilize and ultimately destroy the bacteria.

“Our findings suggest that these previously overlooked molecules could be key players in the immune system’s response to infection,” said a Presidential Associate Professor in Psychiatry, Microbiology, Chemistry, Chemical and Biomolecular Engineering, and Bioengineering, who led the . “This may not only redefine how we understand immunity but also opens up new possibilities for treating drug-resistant infections.”

Expanding the scope of immunity

Traditionally, the immune system was thought to rely primarily on proteins explicitly linked to immune functions. Immune proteins, often referred to as antibodies, are special proteins created by the immune system to detect and combat pathogens such as bacteria and viruses.

However, the new research reveals that structural proteins, along with those structural proteins involved in the nervous systems and systems related to sight, also contribute to antimicrobial defenses. This broader reliance on diverse proteins suggests a more intricate and versatile immune response than previously recognized.

To explore this, the research team formulated what they call the “Cross-talk Hypothesis” to test the notion that non-immune proteins and peptides are communicating or interacting with the immune system in ways previously unrecognized, contributing to its overall function.

They produced peptides derived from non-immune human proteins and assessed their antimicrobial activity. Remarkably, nearly 90 percent of these peptides demonstrated significant antimicrobial properties, particularly by disrupting bacterial membranes. Additionally, peptides sourced from the same anatomical regions as the site of infection exhibited enhanced efficacy when used together, indicating potential synergistic effects.

This breakthrough suggests that the immune system leverages a broader toolkit than once thought, opening new avenues for combating antibiotic-resistant infections.

Promising preclinical results

In mouse models, eight of the synthesized peptides showed notable anti-infective activity, leading to a significant decrease in bacterial infections. Beyond their antimicrobial effects, these peptides also displayed immunomodulatory properties—those which modify or regulate the immune system's response—affecting important inflammatory mediators crucial for the body’s response to infections.

A new approach in the fight against antibiotic resistance

The discovery comes at a critical time. The poses a significant global health threat, responsible for more than 1.3 million deaths annually, and  suggests that as many as 39 million people will die from antibiotic-resistant infections by 2050. By leveraging the body’s natural defenses through these non-immune proteins, researchers hope to develop therapies that are both effective and less prone to resistance.

The co-first authors of the study are Marcelo Torres, a research associate, and Angela Cesaro, a postdoctoral fellow. Research reported in this publication was supported by the Langer Prize (AIChE Foundation), the NIH R35GM138201, and DTRA HDTRA1-21-1-0014.

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