Groundbreaking discovery links phage DNA modifications to fighting superbugs
In a collaborative breakthrough, researchers have uncovered a novel type of DNA modification in bacteriophages (phages) that could bolster the effectiveness of phage therapy against antibiotic-resistant bacteria. The international team, including scientists from SMART AMR (Singapore-MIT Alliance for Research & Technology), the University of Otago, NTU Singapore, Delft University of Technology, University of Canterbury, and MIT, identified phage DNA modified with arabinose sugars added to cytosine. This modification, which can form double or triple arabinosylated DNA through additional cellular steps, appears to shield phage DNA from bacterial defense systems.
What makes these modifications important?
Bacteria possess sophisticated defense networks—such as restriction-modification (RM) systems and CRISPR-Cas—that detect and destroy invading phage DNA. In response, phages have evolved countermeasures, including chemical modifications to their own genomes. The new arabinosylation of cytosine represents a distinct strategy to evade bacterial DNA-sensing and restriction mechanisms, increasing phage survival and therapeutic potential.
Key findings and implications
The study, reported in Cell Host & Microbe under the title “Phage arabinosyl-hydroxy-cytosine DNA modifications result in distinct evasion and sensitivity responses to phage defense systems,” demonstrates that higher levels of arabinose modification correlate with greater protection against bacterial defenses. Importantly, many of the modified phages target major pathogens, including Acinetobacter baumannii (A. baumannii), a WHO-listed critical priority pathogen notorious for hospital-acquired infections and multi-drug resistance.
Why this matters for antibiotic-resistant infections
A. baumannii causes pneumonia, meningitis, sepsis, and urinary, blood, and wound infections. Its ability to resist multiple drugs leaves clinicians with limited treatment options. The newly described DNA modifications offer a twofold advantage: they improve phage persistence in hostile bacterial environments and potentially enable the development of highly targeted phage therapies against resistant strains, reducing collateral damage to beneficial microbiota.
Researchers’ perspectives and the path forward
Dr. Liang Cui, Principal Research Scientist at SMART AMR, emphasizes that the interactions between phages and bacteria are far more complex than previously thought. “A better understanding of these interactions is key to using phages to fight bacterial infections,” Cui notes. The team leveraged a highly sensitive analytical platform developed at SMART to detect novel phage DNA modifications, revealing that these modifications occur at a higher rate than earlier predictions.
Prof. Peter Fineran from the University of Otago adds that the research not only sheds light on phage biology but also establishes methods for genetically engineering phages with DNA modifications. This capability could accelerate the development of phage therapeutics as viable tools against antibiotic-resistant pathogens, turning the ongoing phage-bacteria arms race into a driving force for medical innovation.
Beyond therapy: broader scientific impact
By revealing a richer diversity of phage DNA modification systems, the study revises fundamental assumptions about phage biology and opens new directions for discovery. The interdisciplinary approach, combining analytics, genomics, informatics, and molecular biology, underscores how collaborative science can translate basic knowledge into practical healthcare solutions.
Looking ahead
The research team plans to explore the newly identified modification systems further, aiming to understand how phage DNA chemistry influences interactions with diverse bacterial hosts. The ultimate goal is to harness these insights to improve phage therapies, offering targeted, effective options against antibiotic-resistant infections and reducing the global burden of antimicrobial resistance.
