Understanding how a bacteriophage protein inhibits bacterial cell wall synthesis

Ikoma, Japan—Drug-resistant bacteria are becoming more common worldwide, posing a major public health challenge. Addressing this problem requires finding new ways to eliminate bacteria, which in turn requires analyzing essential cellular processes that could serve as targets for future antibiotics.

Nature may offer some clues in viruses known as bacteriophages, or “phages”. These viruses infect bacteria and hijack their cellular machinery to replicate. Some of them even inject small proteins that shut down specific bacterial processes, ultimately causing the cell to die. One target is MurJ, a protein that bacteria use to transport lipids needed to build their cell wall. Although several bacteriophage proteins that can inhibit MurJ have been found, their amino acid sequences can be quite varied. How can such different proteins block the same essential target, and do they use the same molecular strategy?

To answer these questions, a research team led by Assistant Professor Hidetaka Kohga of Nara Institute of Science and Technology (NAIST), Japan, examined how a bacteriophage protein called Sgl^PP7 inhibits MurJ. Their study, which was published in PLOS Biology on October 27, 2026, reveals the finer details of how Sgl^PP7 interacts with MurJ and compares its inhibition mechanism with those of other phage proteins that target the same lipid transporter. Co-authors included Mr. Kaito Hosoda, Mr. Sixian Wu, Mr. Hiroyuki Tanaka, Dr. Hideki Shigematsu, Assistant Professor Ryoji Miyazaki, Associate Professor Min Fey Chek, and Professor Tomoya Tsukazaki, all from NAIST.

The researchers used cryo-electron microscopy, a technique that reveals the structures of biological molecules at near-atomic resolution, to determine the structure of the MurJ– Sgl^PP7 complex. They also performed experiments involving targeted protein mutations, bacterial cell lysis, and computer simulations to investigate how the interaction with Sgl^PP7 affects MurJ’s behavior.

The results showed that Sgl^PP7 lies along a lipid-binding groove in MurJ and inserts its short C-terminal tail into a deep internal cavity. This interaction stabilizes MurJ in an outward-facing conformation, preventing it from completing the back-and-forth structural changes required to transport lipid. Comparisons with two other known phage proteins, Lys^M and Sgl^CJ3, revealed that all three stabilize a similar conformation of MurJ despite binding to it in different ways. “These findings suggest convergent evolution toward a common target through diverse inhibitory mechanisms,” says Dr. Kohga.

Understanding these interactions could help researchers design new drugs and engineer artificial phage proteins with targeted antibacterial activity. “By revealing how phage proteins inhibit MurJ, this study provides a foundation for drug discovery targeting this transporter,” explains Dr. Kohga. “Although still at the basic research stage, these findings could contribute to the development of new antibacterial agents against drug-resistant bacteria.”

Further research efforts in this field will hopefully shed light on antibacterial mechanisms that evolved naturally and bring us closer to a new generation of antibiotics.

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Resource

Title: Structural basis for inhibition of the lipid flippase MurJ by phage lysis protein Sgl^PP7 suggests convergent evolution with other Sgl peptides

Authors: Kaito Hosoda, Hidetaka Kohga, Sixian Wu, Hiroyuki Tanaka, Hideki Shigematsu, Ryoji Miyazaki, Min Fey Chek, and Tomoya Tsukazaki

Journal: PLOS Biology

DOI: 10.1371/journal.pbio.3004039

Information about Structural Life Science (Tsukazaki Lab) can be found at the following website: https://bsw3.naist.jp/tsukazaki/en.html

About Nara Institute of Science and Technology (NAIST), Japan

Established in 1991, Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Known as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become tomorrow's leaders in science and technology.