Bacteriophages Offer New Hope in Fight Against Antibiotic Resistance
A growing global crisis fueled by antibiotic-resistant bacteria is driving scientists to explore alternative infection treatments, with viruses that prey exclusively on bacteria – known as bacteriophages – taking center stage. New research from the University of Murcia (UMU) is providing critical insights into how these viruses evade bacterial defenses, potentially unlocking a new generation of therapeutic tools.
According to estimates cited by researchers, 4.7 million deaths worldwide were linked to antibiotic resistance in 2021, with 1.2 million directly attributable to resistant infections. “Increasingly, we are seeing cases of patients with infections for which there is no effective antibiotic treatment,” explained a senior researcher. While the search for new antibiotics continues, the pace of discovery is slow, with few new drugs reaching the market in recent years.
The Rise of Phage Therapy
Bacteriophages, or phages, are viruses that specifically infect and kill bacteria, leaving human cells unharmed. They are remarkably specific, often targeting particular species or even strains within a species. This precision, researchers note, helps preserve the body’s beneficial microbiota. However, this specificity also presents a challenge: a phage effective against one strain may be useless against a closely related one.
This variability is the result of an ongoing “arms race” between bacteria and viruses. Bacteria have evolved multiple defense systems to protect themselves from phage attacks, while phages, in turn, accumulate mutations and strategies to overcome these barriers. “The struggle between bacteria and phages has led to the development of this variety of systems in bacteria and the acquisition of evasion mechanisms by phages,” a researcher stated. Understanding this competition is key to predicting whether a virus can successfully infect and eliminate a specific bacterium.
CRISPR and Restriction-Modification Systems: Bacterial Defenses
The study of bacterial defenses has had far-reaching implications beyond basic microbiology. The CRISPR-Cas system, discovered by Spanish researcher Francis Mojica, functions as an immune memory against viral infections and formed the basis for Nobel Prize-winning gene editing techniques. Another crucial system, less widely known but vital in biotechnology, is the restriction-modification (RM) system.
RM systems act as a molecular recognition mechanism. They consist of a methylase that modifies specific short DNA sequences within the bacterium, marking them as “safe,” and a restriction enzyme that cuts those same sequences if they are not modified. When a phage infects a bacterium with an RM system, its DNA, lacking these modifications, is typically recognized and fragmented, halting the infection. For decades, the presence or absence of these target sequences in the phage genome has been used to predict its ability to overcome this defense.
A New Perspective on Phage Evasion
The recent work led by the UMU team introduces a new nuance to this understanding. In collaboration with researchers from the University of Otago and the University of Waikato, the team demonstrated that the location of these sequences within the viral DNA is just as important as their presence. The study reveals that phages lacking RM system targets in the region of their genome that enters the bacterium first can successfully complete infection, even if those sequences appear later in other parts of the viral DNA.
“Generally, researchers looked for targets in any region of the genome to predict a phage’s ability to infect a bacterium with RM systems,” explained a researcher. This finding challenges that broad approach, requiring a focus on the temporal organization of the viral genome during infection. The initial region of the phage’s DNA acts as an “advance guard,” successfully entering without being attacked, allowing the rest of the genome to follow, even carrying sequences that would normally trigger a defensive response.
To illustrate this mechanism, a researcher used a military analogy: the absence of the target in the initial region “would serve as a bridgehead acting on the RM system so that it does not attack when the phage inserts the rest of the genome even if it has target sequences, that is, allowing the entry of the rest of the invading army.” While the precise molecular mechanism behind this RM system inhibition is still under investigation – a line of inquiry being pursued in the doctoral thesis of Andrea Martínez Cazorla – the functional effect is clearly demonstrated.
Implications for Phage Therapy Development
These findings have significant implications for the development of phage therapy. A major challenge in the field is predicting a virus’s effectiveness against a specific pathogen. According to researchers, phages that consistently insert the same genomic region at the beginning of the infectious cycle “can be specifically analyzed in that zone to detect the presence of RM system targets.” If present, that phage will likely be ineffective against bacteria with that defense system.
Furthermore, this knowledge opens the door to the rational design of phages through genetic engineering. “It is possible to generate phages with certain changes in their DNA sequence that eliminate the target sequences, without these changes affecting protein synthesis,” a researcher noted. Adjusting the architecture of the viral genome to evade specific bacterial defenses could increase the efficacy and safety of future clinical applications.
While phage therapy is gaining increasing interest, its routine incorporation into European healthcare systems still faces obstacles, particularly regulatory ones. In Spain, its use “is currently limited to compassionate cases, in patients for whom all conventional antibiotic treatments have failed, and requires specific authorizations.” Initiatives like the Fagoma network, which includes the UMU group, are working to raise awareness of the need to overcome these barriers. In the meantime, phages are also being explored in other areas, such as agriculture, livestock farming, aquaculture, and the food industry.
