Viruses Target Bacterial Cell Walls: New Hope for Antibiotics

The escalating crisis of antibiotic resistance may have met a surprising ally: viruses that infect bacteria. A novel study, published in the journal Nature on February 26, reveals a shared mechanism by which different viruses disable a crucial bacterial protein, MurJ, offering a potential new avenue for antibiotic development. The findings highlight a bacterial vulnerability that evolution itself seems to repeatedly target, suggesting a promising path forward in the fight against superbugs.

The Growing Threat of Antibiotic Resistance

Antibiotic resistance is a rapidly worsening global health threat. As bacteria evolve, they become less susceptible to existing drugs, rendering infections harder – and sometimes impossible – to treat. “Evolution is powerful, and in bacteria, resistance to antibiotics develops quickly,” explains Bil Clemons, the Arthur and Marian Hanisch Memorial Professor of Biochemistry at Caltech and the corresponding author of the study. “In other words that we now deal with bacteria that are resistant to all the medicines that we have. In the USA alone, tens of thousands of people die every year from antibiotic-resistant bacterial infections, and that number is rising rapidly. We need new antibiotics to combat this.”

Targeting the Bacterial Cell Wall: A Long-Held Strategy

Scientists have long focused on the bacterial cell wall as a potential target for new antibiotics. Unlike human cells, bacteria possess a unique structure called peptidoglycan, which provides strength and rigidity. Disrupting the production of peptidoglycan can kill bacteria without harming human cells. The process of building this cell wall, known as the peptidoglycan biosynthesis pathway, has been extensively studied, and several existing antibiotics, like penicillin discovered by Alexander Fleming, interfere with different stages of this pathway. EurekAlert! provides further details on this background.

MurJ: A Key Player in Cell Wall Construction

Recent research has honed in on three essential proteins – MraY, MurG, and MurJ – that are critical for transporting the building blocks of peptidoglycan across the bacterial inner membrane. If any of these proteins are blocked, the cell wall cannot be assembled, and the bacterium dies. Even as the overall function of these proteins is understood, the precise mechanisms by which they operate have remained somewhat elusive. Currently, no approved drugs directly inhibit these three proteins, but researchers believe they hold significant potential as antibiotic targets.

How Bacteriophages Offer Clues

The breakthrough came from studying bacteriophages – viruses that infect and kill bacteria. To replicate, phages must breach the bacterial cell wall. Clemons explains that phages need to overcome the peptidoglycan layer to escape and infect other bacteria. The Caltech team focuses on small phages with simple genomes, which rely on efficient strategies to disable their hosts. Their previous work, published in Science in 2023, examined the phage φX174, a long-studied virus at Caltech. Caltech News details this earlier research.

Convergent Evolution and the Sgl Proteins

The study centers on a class of viral proteins called single-gene lysis proteins, or Sgls. These proteins are deployed by phages to kill bacteria. Researchers, led by Yancheng Evelyn Li, a graduate student in Clemons’ lab, focused on Sgls that target MurJ. Previous research had already identified two unrelated Sgls, SglM and SglPP7, that could kill bacteria by blocking MurJ’s function.

Using cryo-electron microscopy at Caltech’s Beckman Institute, Li discovered that both SglM and SglPP7 attach to the same groove on MurJ, effectively locking it in place and preventing it from transporting peptidoglycan precursors. This outward-facing conformation of MurJ is particularly encouraging because it’s exposed and potentially more accessible to drug molecules.

What surprised researchers most was the discovery of a third Sgl protein, SglCJ3, identified through analysis of another phage genome. Remarkably, SglCJ3 also binds to MurJ in the same way, locking it in the outward-facing conformation. “These peptides, which have no evolutionary links to each other, have both figured out how to target MurJ in a highly similar way,” Clemons says. “These are two examples of convergent evolution, in which different evolutionary paths arrive at the same solution. We were surprised!” This convergence suggests that MurJ is a particularly vulnerable target, repeatedly identified by evolution as a critical point to disrupt.

Implications for Antibiotic Discovery

The discovery that multiple, unrelated viruses have independently evolved mechanisms to target MurJ provides a strong rationale for developing new antibiotics that mimic these viral strategies. The researchers believe that studying the genomes of more phages could reveal additional Sgl proteins and further refine our understanding of how to effectively inhibit MurJ. Phys.org provides a PDF version of the study findings.

Future Directions and Research

The team is now focused on leveraging these discoveries to design and synthesize small molecule drugs that can inhibit MurJ. “Our path is set on leveraging Sgl discovery, and we hope to continue to be supported to turn these concepts into realities,” Clemons states. Further research will be needed to assess the safety and efficacy of these potential new antibiotics, but the initial findings offer a significant step forward in the ongoing battle against antibiotic-resistant bacteria. The research was supported by the Chan Zuckerberg Initiative, the National Institutes of Health, the G. Harold and Leila Y. Mathers Foundation, and the Center for Phage Technology at Texas A&M.