New class of encoded peptides offers hope against drug-resistant bacteria

In a major advance against the growing threat of antibiotic-resistant bacteria, researchers have identified a new class of antimicrobial agents known as cryptic peptides, which may expand the immune system’s arsenal of infection-fighting tools. The findings, published today in Trends in Biotechnology 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 César de la Fuente, PhD, Presidential Associate Professor of Psychiatry, Microbiology, Chemistry, Chemical and Biomolecular Engineering, and Industrial Engineering, who led the research team.”This may not only redefine how we understand immunity, but also open up new possibilities for treating drug-resistant infections.”

Broadening the scope of immunity

Traditionally, the immune system has been thought to rely primarily on proteins specifically associated with immune functions. Immune proteins, often referred to as antibodies, are special proteins made by the immune system to detect and fight pathogens such as bacteria and viruses.

However, new research reveals that structural proteins, along with those structural proteins involved in nervous and vision-related systems, also contribute to antimicrobial defense. This broader reliance on different proteins suggests a more complex and versatile immune response than previously recognized.

To investigate this, the research team formulated what they call the “Cross-talk Hypothesis” to test the idea that non-immune proteins and peptides communicate or interact with the immune system in previously unrecognized ways, contributing to overall function of.

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

This discovery suggests that the immune system taps into a wider toolbox than we once thought, opening new ways to fight antibiotic-resistant infections.

Promising preclinical results

In mouse models, eight of the synthesized peptides showed remarkable anti-infective activity, leading to a significant reduction in bacterial infections. In addition to their antimicrobial effects, these peptides also exhibited immunomodulatory properties—those that modify or modulate the immune system’s response—by affecting important inflammatory mediators vital to the body’s response to infections.

A new approach to combating antibiotic resistance

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

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