New research from Indiana University has uncovered a previously unknown vulnerability in how bacteria build the whip-like tails they use to move. The researchers found that building these tails can put stress on the protective wall surrounding a bacterial cell, and uncovered systems bacteria use to keep that stress from becoming destructive.
The discovery, published in the Proceedings of the National Academy of Sciences, reveals an unexpected connection between the way bacteria move and the way they maintain the wall that keeps their cells intact, findings that could help scientists find new ways to fight bacterial infections, especially at a time when drug resistant bacteria are a growing public health threat.
The study comes from the lab of Daniel Kearns, Professor of Biology in the College of Arts and Sciences at IU Bloomington, and was co-led by two researchers in the Biology department, Caroline Dunn and Kehinde Adebiyi. Their experiments focused on Bacillus subtilis, a harmless soil bacterium that scientists have long used as a stand-in for studying how bacteria build complex structures, including structures used by bacteria that cause disease.
Many disease-causing bacteria, including strains of E. coli, Salmonella and Listeria, rely on a spinning tail called a flagellum to swim through fluids in the body, reach tissue and spread infection. To build that tail, a bacterium has to push a series of parts through its own cell wall, a tough, mesh-like layer made of a material called peptidoglycan. That wall keeps water from rushing in and bursting the cell open, and it is also the same structure that many existing antibiotics, including penicillin, are designed to attack.
Learning exactly what happens to that wall while a flagellum is being built helps scientists understand how bacteria overcome the challenge of getting various structures through their important cell wall. It could also reveal a new vulnerability that future drugs might exploit, potentially stopping infections before they start.
Scientists had proposed that bacteria solve this problem because the cell wall isn’t perfectly uniform. It naturally contains gaps of different sizes scattered across its surface, and the flagellum’s building blocks are thought to search until they find a gap wide enough to fit through. Dunn and Adebiyi set out to directly test that idea.
The researchers removed a cell wall building protein called PBP1, which might normally repair small gaps in the wall, expecting that fewer patches might create more open holes in which flagella might fit. Instead, something unexpected happened. Without PBP1, the bacteria began dying in large numbers, and the deaths lined up directly with flagellum construction.
“We expected removing PBP1 might make flagellar assembly less regulated, not lethal,” Dunn said. “Watching cells begin to burst open as soon as the flagellum was built told us we had revealed something the field hadn’t seen before.”
Through a lengthy series of genetic experiments, the team traced the cause. Once a piece of the flagellum, called the hook, is finished, it flips a genetic switch inside the bacterium that activates a set of enzymes that break down the bacterium’s own cell wall. Some of that wall-breaking might help the flagella to position and spin properly but it also creates damage that PBP1 is thought to repair. PBP1 patches that damage as fast as it happens, keeping the wall intact. Without PBP1 present, however, the researchers found that the wall breaks down faster than the bacterium can recover, and the bacterium splits open and dies.
“The exciting part of this work is that a structure we normally think about only in terms of movement can actually create a vulnerability in the bacterial cell envelope,” Adebiyi said. “Our findings show that flagellar assembly and cell-wall maintenance are much more connected than we previously appreciated.”
The paper itself underscores just how much this reframes earlier assumptions about the flagellum. As the researchers write, flagella, “not normally thought to impact cell viability, can be toxic” to the cell that builds them. The research offers a striking reminder of how much remains unknown about processes scientists have studied for generations.
The implications reach beyond one harmless soil bacterium. Many disease-causing bacteria build large structures that must cross the cell wall in a similar way, including tools some bacteria use to inject toxins into human cells. If those structures carry a similar hidden risk to the bacterial cell wall, understanding how cells manage that risk could eventually help researchers design drugs that target the same vulnerability, disrupting a bacterium’s ability to build the tools it needs to move, invade and spread. Discovery of this kind matters at a time when many bacteria are growing harder to treat with existing antibiotics.
Support for this research included National Institutes of Health grants to Kearns and to the Indiana University Light Microscopy Imaging Center, which provided the specialized microscopy used throughout the study.
The College of Arts