April 15, 2025

The very first structural images of a tuberculosis-fighting virus New insights from Scripps Research could advance phage therapies for the world's deadliest bacteria including drug-resistant strains.

April 15, 2025

LA JOLLA, CA Mycobacteria are the world's most deadly bacteria causing infectious diseases including tuberculosis (TB), which alone kills more than one million people each year. New drugs to fight these infections are desperately needed, as the number of cases of antibiotic-resistant mycobacteria is on the rise.

Scientists at Scripps Research and the University of Pittsburgh have now used advanced imaging techniques to provide a detailed look at how a tiny virus, known as a phage, invades Mycobacteria. The research, published in Cell on April 15, 2025, could pave the way toward phage-based treatments for antibiotic-resistant mycobacteria.

Phages have evolved over millions of years to precisely target specific bacteria, says Scripps Research assistant professor Donghyun Raphael Park, a co-senior author of the new work. But to be able to develop phages into effective therapies, we need to know more about how they interact with Mycobacteria.

Phage therapies, which use viruses to attack drug-resistant bacteria, are gaining attention as potential alternatives to antibiotics. Because they recognize different aspects of bacteria than typical antibiotics, they may be able to kill pathogens that have evolved to avoid recognition by the standard drugs. But the phages that target Mycobacteria known as mycobacteriophages have remained poorly understood. Scientists have had little insight into the phages' structures and how they recognize and infect Mycobacteria.

Park teamed up with other researchers, including Graham Hatfull of the University of Pittsburgh and Howard Hughes Medical Institute, to answer these questions and create atomic-level models of the mycobacteriophage known as Bxb1.

The team combined data from single particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET), two imaging techniques that allow researchers to visualize frozen biological structures at near-atomic resolution. They captured images at multiple stages of infection revealing how Bxb1 attaches to Mycobacteria, injects its genetic material and begins the infection process. The results were surprising.

Other phages form a channel through the bacterial membrane to inject their DNA, so we expected to see the same here, Park said. But we didn't. This suggests mycobacteriophages use a completely different genome translocation mechanism.

Myobacteria have particularly thick and unusual cell walls compared to other bacteria, and Park said more work is needed to uncover how phages are able to inject their genome through this formidable and seemingly impenetrable cell wall.

The new structures also revealed how the tail tip of the phage dramatically changed when it bound to the bacteria, providing insights into the dynamic process of infection. Park hopes that detailing the structures of other mycobacteriophages can shed light on what structural elements such as this tail tip are most important. While he doesn't plan to work out the structures of all of the thousands of phages that could fight Mycobacteria, his lab will focus on a few more and delve into studies linking the phages' structures to their functions. This could guide the rational selection of phages for treating Mycobacteria, helping researchers identify which phages work best for antibiotic-resistant TB and lead toward the design of effective phage therapy.

There are thousands of mycobacteriophages out there, but we don't yet fully understand how they recognize and kill Mycobacteria, Park says. By continuing to study their structures, we can start to identify the hallmarks of an effective phage and design better treatments.

In addition to Park and Hatfull, authors of the study, Structure and infection dynamics of mycobacteriophage Bxb1, were Sudipta Mondal, Benjamin Silva and Valery Ortiz of Scripps; Krista Freeman, Deborah Jacobs-Sera, Alexis Huet, and James Conway of University of Pittsburgh; Lourriel Macale, Ronelito Perez, Joemark Narsico, Meng-Chiao Ho, and Todd Lowary of Academia Sinica; Jennifer Podgorski and Simon White of University of Connecticut.

This work was supported by funding from the National Institutes of Health (GM116884, K99AI173544, U24GM129547), the Howard Hughes Medical Institute (GT12053), the Scripps Research start-up fund, the Bachrach Family Foundation, and Academia Sinica.

Integrative Structural & Computational Biology Park, Donghyun Raphael

LINK:	https://www.scripps.edu/news-and-events/press-room/2025/20250415-park-...
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