Researchers have identified a sophisticated dual-function molecular machine in bacteria that simultaneously controls how they move and how they acquire new genetic material, a process crucial for the spread of antibiotic resistance. The discovery, detailed in a new study, provides an unprecedented, near-atomic-level view of how a single protein complex can switch between powering locomotion and facilitating DNA transfer, offering a promising new target for future antimicrobial therapies.
This breakthrough, led by a collaboration of scientists from the University of Basel in Switzerland and the University of Freiburg in Germany, resolves a long-standing question in microbiology. It was known that many bacteria use grappling hook-like appendages called Type IV pili (T4P) for both movement and genetic exchange, but the precise mechanism linking these two vital functions was unclear. The new findings reveal a molecular “clutch” that allows the bacterial machinery to elegantly shift gears between pulling the cell forward and opening a channel for DNA uptake.
Understanding this mechanism is critical. Bacterial motility allows pathogens to colonize hosts and form resilient biofilms, while horizontal gene transfer is the primary way bacteria share traits like antibiotic resistance. By showing how these processes are physically coupled, the study illuminates a key strategy that has made bacteria one of the most adaptable life forms on Earth and presents a potential vulnerability that could be exploited to combat drug-resistant infections.
A Molecular Machine with Two Functions
The focus of the investigation was the Type IV pilus system, a remarkable piece of natural nanotechnology. Pili are thin, hair-like filaments that extend from the bacterial surface. They can attach to surfaces or other cells and then retract, pulling the bacterium along in a form of movement called “twitching motility.” This same machinery is also co-opted for DNA transfer during processes like transformation (uptake of free DNA from the environment) and conjugation (direct transfer from another bacterium).
The research team, using the soil bacterium Myxococcus xanthus as a model organism, employed cutting-edge imaging techniques to visualize the entire T4P motor complex in its native state, embedded within the bacterial cell membrane. What they discovered was a dynamic, multi-protein assembly that changes its structure to perform different tasks.
At the heart of this system is a powerful motor protein, known as PilT, which acts like a winch. When the system is in “motility mode,” the PilT motor engages with the pilus filament and, by hydrolyzing ATP for energy, rapidly retracts it, pulling the cell forward with forces equivalent to many times its own weight. The new research revealed that a previously uncharacterized accessory protein, which the team has functionally described, acts as a regulatory clutch. When this protein is engaged, it causes a subtle but significant conformational change in the entire complex. This shift disengages the primary retraction function and instead widens a central pore within the machine, creating a stable channel wide enough for a strand of DNA to pass through the cell envelope and into the cytoplasm.
Advanced Imaging Reveals the Switch
The visualization of this molecular switch in action was made possible by a powerful combination of imaging and computational modeling technologies. The primary tool was cryo-electron tomography (cryo-ET), a technique that involves flash-freezing living cells to preserve their internal structures in a near-native state. By taking thousands of images from different angles and computationally combining them, the scientists were able to reconstruct a high-resolution 3D model of the T4P machine as it operated inside the cell.
“Seeing the structure change between the two states was the definitive moment,” the lead author, Dr. Anja Weber of the University of Basel’s Biozentrum, was paraphrased as stating in a university press release. “It’s a stunningly efficient piece of molecular engineering, where a single motor complex is repurposed for two fundamentally different jobs with just a minor rearrangement of its parts.”
To pinpoint the active machines within the crowded cellular environment, the team also used a technique called correlative light and electron microscopy (CLEM). This allowed them to first identify bacteria actively undergoing DNA uptake using fluorescent markers and then zoom in on those specific cells for high-resolution cryo-ET imaging. Molecular dynamics simulations were then used to model the energy landscapes and predict how the components move during the functional switch.
Implications for Combating Antibiotic Resistance
The discovery of this molecular clutch has profound implications for public health. The global rise of antibiotic-resistant “superbugs” is a major crisis, driven largely by the ability of bacteria to rapidly acquire and share resistance genes via horizontal gene transfer. The new research suggests a novel therapeutic strategy: instead of killing the bacteria outright, it may be possible to disarm them.
The key findings of the study include:
- Structural basis of the dual function: The first direct visualization of the T4P machine in both a motility-competent and a DNA-uptake-competent state.
- Identification of a molecular switch: A specific protein component was identified as the key regulator or “clutch” that controls the transition between the two functions.
- A unified mechanism: The research demonstrates that the same core motor provides the power for both pilus retraction and DNA translocation, unifying the two processes under a single mechanical framework.
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A drug designed to target and “jam” this clutch mechanism could potentially achieve two goals at once. It could immobilize the bacteria, preventing them from colonizing surfaces and forming biofilms, which are notoriously difficult to treat. Simultaneously, it could block the primary gateway for acquiring new resistance genes, effectively slowing down their evolution and preserving the efficacy of existing antibiotics. Such a drug would represent an “anti-virulence” or “anti-evolution” therapy, a promising alternative to traditional bactericidal antibiotics, which often place strong selective pressure on bacteria to evolve resistance.
Next Steps and Broader Context
The research team plans to expand on these findings by screening for small-molecule compounds that can inhibit the newly identified switching mechanism. They also aim to determine if this dual-function system is conserved across a broader range of pathogenic bacteria, such as Pseudomonas aeruginosa and Neisseria gonorrhoeae, which also rely on T4P systems for infection.
While the study provides a remarkable new level of detail, researchers caution that translating this fundamental discovery into a clinical application is a long-term goal. The exact structure and regulation of the T4P system may vary between different bacterial species, and any potential drug would need to be highly specific to avoid off-target effects.
Nonetheless, by decoding the fundamental mechanics of how bacteria move and evolve, this work lays a critical foundation. It provides a detailed blueprint of a key vulnerability, offering a new and strategic direction in the ongoing battle against infectious diseases.