Revived Ancient Proteins Offer New Insights into Combating Antibiotic Resistance

Biologists at the University of Oregon have made a significant breakthrough by reviving proteins that are about 160 million years old, which demonstrate natural antimicrobial properties. This exciting development could pave the way for innovative strategies to tackle antibiotic-resistant infections—an escalating global health crisis.

Details of the research were published in a recent edition of PLOS Biology on August 25. The study involved tracing the evolutionary lineage of peptides—short protein fragments—back to the origins of placental mammals, which include most of the animals we are familiar with today, including humans. Notably, peptides reconstructed from long-lost ancestors exhibited greater efficacy against drug-resistant bacteria compared to their modern counterparts.

As Matt Barber, the study's senior author and an evolutionary biologist at the University of Oregon's College of Arts and Sciences, noted, the evolution of bacteria continues to threaten the effectiveness of antibiotics. "Antibiotics have been pivotal in modern medicine," he remarked, "but bacteria have consistently adapted and developed resistance." As the research team looks ahead, they're eager to explore how enhanced antimicrobial peptides from ancient sources can potentially become viable treatments in the future.

During the late Jurassic period, around 160 million years ago, the common ancestor of all placental mammals emerged, marking a key point in the evolutionary timeline. Simultaneously, lactoferrin—a specific immune protein central to this study—appeared. Present in nearly every body fluid except blood, lactoferrin plays a crucial role in iron sequestration, effectively starving bacteria of the essential nutrient they require for growth.

Interestingly, lactoferrin is equipped with its own form of defense against pathogens, containing an antimicrobial peptide that can damage bacterial membranes, leading to cell rupture. Titas Sil, the lead author and a doctoral student in Barber’s team, emphasized, “Antimicrobial peptides are essential components of the body's first line of defense; their potential for therapeutic application is significant.”

The research highlighted a notable distinction between close relatives of lactoferrin, which do not share this antibacterial capacity. This difference suggests that the antimicrobial ability evolved subsequently in mammalian history. Barber's team meticulously retraced the evolutionary pathway to ascertain how and when this vital trait developed, generating reconstructions of lactoferrin from its extinct ancestors.

Barber characterized evolution as a vast repository of biological experimentation. "It's essentially a billion-year-old science experiment," he expressed, underscoring how the outcomes of natural selection can guide modern medical advancements.

To achieve the reconstruction of ancient antimicrobial peptides, Sil initially compared lactoferrin gene sequences from existing species like humans and cows. By mapping the evolutionary connections among these sequences, she employed statistical methodologies to infer the genetic constructs carried by their common ancestors, extending this analysis back roughly 160 million years.

The research team applied a method known as ancestral sequence reconstruction, first developed by Joseph Thornton, a previous member of UO's faculty. Sil synthesized these ancient genes, producing the reconstructed proteins in cellular environments and subsequently testing their efficacy against several pathogens related to human diseases, including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Streptococcus.

The earliest revived peptides exhibited the capability to disturb bacterial membranes; however, these bacteria were still able to repair themselves and survive. On the other hand, peptides reconstructed from more recent ancestors displayed increasingly better performance, at times surpassing the efficiency of the corresponding modern human peptides.

A key finding emphasized by Barber was that subtle structural variations, specifically one mutation in the amino acid chain, drastically enhanced the antimicrobial effectiveness of these peptides. "What stood out was how minor adjustments could yield significant results," he noted. While clinical trials have previously explored derivatives of human lactoferrin for treating infections, the study revealed that even minimal changes could potentially elevate the activity of peptides beyond contemporary human versions.

Despite their promise, Barber and Sil caution that ancient antimicrobial peptides are not yet suitable for immediate medicinal use. Unlike traditional antibiotics, these peptides tend to be less stable structurally and are rapidly degraded within the human body.

Nonetheless, the study opens the door to developing strategies to counteract the challenge of bacterial resistance. By examining how antimicrobial peptides have evolved across millions of years, researchers may glean insights into creating modern therapeutics that are less susceptible to resistance.

Barber emphasized the need for foresight in this research area: "Pathogens are likely to evolve resistance against these new peptides as well. But understanding their evolutionary adaptations will be crucial in formulating better-targeted treatments and effective combination therapies to mitigate resistance."

This research was supported by the National Institutes of Health.

Material provided by University of Oregon. The original article was authored by Leila Okahata and may have been edited for clarity and length.