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Mycobacteria are among the most lethal bacteria globally, responsible for infectious diseases such as tuberculosis (TB), which claims over one million lives annually. The urgent need for new treatment options has intensified, particularly as the prevalence of antibiotic-resistant strains of mycobacteria continues to grow.
In a significant advancement, researchers from Scripps Research and the University of Pittsburgh have utilized cutting-edge imaging technologies to comprehensively study how a specific type of virus, known as a phage, infiltrates Mycobacteria. This groundbreaking research, published in Cell on April 15, 2025, may offer innovative phage-based therapeutic strategies against antibiotic-resistant mycobacterial infections.
“Phages have developed over substantial periods to specifically target certain bacterial strains,” explained Donghyun Raphael Park, an assistant professor at Scripps Research and a co-senior author of the study. “To harness phages for effective treatment, a deeper understanding of their interactions with Mycobacteria is crucial.”
Phage therapy, which employs viruses to combat drug-resistant bacteria, is garnering interest as a plausible substitute for traditional antibiotics. These phages may identify and eliminate pathogens capable of evading conventional antibiotics due to their unique mechanisms of action. However, understanding the characteristics and attacking strategies of mycobacteriophages, which specifically target Mycobacteria, has remained elusive to scientists. There has been limited clarity on the structural properties of these phages and their methods for recognizing and infecting Mycobacteria.
To address these knowledge gaps, Park collaborated with Graham Hatfull from the University of Pittsburgh and the Howard Hughes Medical Institute, aiming to develop atomic-level models for the mycobacteriophage named Bxb1.
The research team employed single particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET)—both advanced imaging techniques that enable the visualization of frozen biological samples at near-atomic resolution. They captured images depicting multiple phases of the infection cycle, illustrating how Bxb1 attaches to Mycobacteria, transfers its genetic material, and initiates infection. The findings were unexpected.
“Traditionally, other phages penetrate bacterial membranes to inject their DNA, so we anticipated observing a similar process here,” said Park. “Instead, we did not detect this mechanism, indicating that mycobacteriophages may employ an entirely different method for genome translocation.”
Given that mycobacteria possess thick and complex cell walls, further investigation is necessary to elucidate how phages manage to deliver their genetic material through these robust and seemingly inaccessible barriers.
The newly obtained structural insights also showed how the tail tip of the phage significantly alters upon binding to the bacterial surface, shedding light on the dynamic nature of the infection process. Park aims to extend this structural analysis to other mycobacteriophages, which could unveil key structural components—like the tail tip—central to the efficacy of these viruses. While not every one of the thousands of phages will be explored, his lab intends to focus on several select ones and examine the relationships between phage structures and their functionalities. Such insights may facilitate the strategic selection of phages for treating Mycobacteria, particularly in managing antibiotic-resistant TB, paving the way for effective phage therapy designs.
“Although there are numerous mycobacteriophages, our comprehension of how they recognize and eliminate Mycobacteria remains incomplete,” Park emphasized. “Through continued structural studies, we can begin to determine the characteristics that define effective phages, ultimately leading to improved therapeutic options.”
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