Research finds antibiotics hidden in proteins of systems other than the immune system | Science

The main heroes of the list of immune system proteins are antibodies, which neutralize or identify foreign substances such as viruses or bacteria, and cytokines, which regulate reactions and communication between cells. But this complex defense system against infection, the leading cause of death in human history before the discovery of antibiotics, has a hitherto unknown secondary player that provides a new vision of the body’s protective shield. Research by a machine biology group at the University of Pennsylvania led by Spaniard Cesar de la Fuente has discovered a new category of antimicrobial agents called encrypted peptides, hidden in molecules with different functions in all parts of the body, including the eyes. . Their research is published today in Trends in Biotechnologyfrom Cell Press.

With this work, De la Fuente’s team has deciphered one of the mysteries hidden in the human proteome, the collection of human proteins. In these molecules, which perform specific functions in all systems, such as the nervous, cardiovascular or digestive systems, chains of amino acids (peptides) were discovered whose role was unknown. “They (the encrypted peptides) are hidden in proteins that we never thought could play a role in the immune system,” explains the biotechnologist. After two years of work, the team found that 98% of the analyzed and sequenced peptides from different parts of the body, including the eye, were found in proteins not previously associated with the body’s defense against pathogens.

The researcher compares these encrypted peptides to what was until recently considered junk DNA, genetic sequences thought to be useless but to which subsequent research has been assigned functions that went undetected.

Encrypted peptides are part of proteins and regularly perform work in various body systems. “But we found that the amino acid chains have additional uses and play an antimicrobial and modulatory role in the immune response,” the researcher simplifies. This is what they call the “crosstalk hypothesis,” where proteins from systems other than the immune system interact to promote the body’s defense.

The team’s approach is that most of the encrypted peptides, in the event of bacterial invasion, form the first line of response against the pathogen. The direct antimicrobial effect is to destroy its membrane in order to weaken it, leaving it without a protective wall. The second action is to modulate or activate an immune action (e.g., calling for reinforcement) to eliminate it.

Of the synthesized peptides, eight (collagenin-3, collagenin-4, zipperin-1, zipperin-2 and immunosins 2, 3, 12 and 13) demonstrated significant anti-infective activity in preclinical mouse models and were able to reduce bacterial infections in the skin and thighs by four orders of magnitude . In terms of their immunomodulatory properties, they activate key inflammatory mediators in response to infections, such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1). “In culture dishes, 90% showed antimicrobial properties,” adds De la Fuente.

Of all the systems analyzed in search of encrypted peptides, one of the most unique is the ocular one. The eyes cannot afford the normal inflammatory response in other organs as this can affect vision. This is the so-called immune privilege.

De la Fuente’s team examined the whites of the eye to find out whether the encrypted peptides acted with this “privilege.” “This is an interesting environment for us, and the results provide an answer to the classic question of how the eye is protected,” explains the researcher.

The discovery of this anti-infective function of the encrypted peptides has two important aspects for further research: one is the discovery of a system complementary to that known to fight microbes, and the second is the possibility of using the identified sequences. develop antibiotics that act on bacteria that have become resistant to them and can cause death.

“These previously unconsidered molecules (peptides) may play a critical role in the immune system’s response to infections. This could not only change our understanding of immunity, but also open up new opportunities to combat drug-resistant infections,” the researcher concludes.

This pathogen survival to existing antibiotics (AMR) “represents a serious threat to global health that is associated with high morbidity and mortality, prolonged hospitalization, and increased health care costs,” according to a review published in the journal Lanceolate microbe, and in which De la Fuente participated along with 11 other researchers.

The Global Burden of Disease study identified six of the most worrisome pathogens from a long list due to their resistance to existing drugs: coli, Staphylococcus aureus, Klebsiella pneumonia, Streptococcus pneumoniae, Acinetobacter baumannii And Pseudomonas aeruginosa. Food poisoning due to variant coli (O157:H7), discovered among customers at the McDonald’s hamburger chain in the US last week, has caused one death and fifty more cases, of which a dozen required hospitalization.

“To counter this threat, it is important to develop innovative antimicrobial strategies, such as drug repositioning in combination with few clinically relevant antibiotics,” says Younes Smani, principal investigator of the bacterial infections group at the Andalusian Center for Developmental Biology (CABD). .), a professor in the Department of Microbiology at Universidad Pablo de Olavide (UPO), who was not involved in the research at the University of Pennsylvania.

Smani conducted a study published in Frontiers in Pharmacologyin which, from a drug used in the treatment of cancer (tamoxifen and its compound raloxifene), they identified 27 thiophene derivatives, of which three compounds showed high antibiotic potential against multi-resistant strains of these bacteria, including two of those considered the most dangerous (Acinetobacter baumannii and Escherichia coli.).

Another area of ​​research is the study of phages, viruses that can kill bacteria. A series of case studies of AMR treated with this therapy produced mixed results: of 20 people treated with phages, most of whom had cystic fibrosis-related infections, 11 had a positive response to therapy. However, only five managed to completely get rid of the infection. Another six received a partial response. The rest did not respond or their results were inconclusive.

For its part, the Cooperative Research Center for Biomaterials CIC biomaGUNE has created a new research group dedicated to bottom-up bioengineering and cell biology (Bottom-up Cell Biology and Bioengineering), which aims to study the molecular processes occurring in bacterial biology. cell, that is, how bacteria form and rearrange their cell walls, divide and communicate with each other or with the host organism. The goal is to understand the biological mechanism and develop new strategies to combat antibiotic resistance.

The research team aims to apply reverse engineering, a process that group director Natalya Baranova described as “the reconstruction of cellular processes from the bottom up, with a bottom-up perspective.” “We dismantle molecular components and rebuild them, just like we do with cars or bridges. In this way, we can learn how nature selected these specific components to be critical, meaning we seek to understand the relationship between molecular composition and ultimate biological function,” he explains.