In a significant advance for microbiology, researchers have captured exceptionally detailed, real-time images of an antibiotic breaching the defenses of a harmful bacterium. The findings reveal a surprising mechanism where the drug, a last-resort antibiotic known as Polymyxin B, tricks the bacterium into shedding its own protective outer layer, a process that proves fatal to the microbe. This discovery challenges long-held assumptions about how this class of antibiotics functions and offers new pathways for developing more effective treatments against drug-resistant infections.
The joint research effort from University College London and Imperial College London provides a granular view of the life-or-death struggle between drug and microbe. By visualizing the attack on individual, living *E. coli* cells, the team demonstrated that the antibiotic’s success is critically dependent on the bacterium’s metabolic state. This insight is crucial in the global fight against antimicrobial resistance, a crisis responsible for more than a million deaths each year. The study, published in *Nature Microbiology*, clarifies the complex interactions that allow polymyxins to defeat some of the most stubborn bacterial pathogens.
A New View of a Last-Resort Antibiotic
Polymyxins are a class of antibiotics used to combat Gram-negative bacteria, a category of microbes notorious for their formidable defenses. Bacteria like *E. coli* possess a complex, two-layered cell membrane that acts as a shield, preventing many drugs from reaching their internal targets. For decades, polymyxins have been a vital tool for clinicians when other antibiotics have failed, but the precise way they breached this bacterial armour was not fully understood. It was generally believed that the drugs punched their way through the membrane, but the new research reveals a more intricate and collaborative process, one that requires participation from the bacterium itself.
Advanced Microscopy Captures the Attack
Atomic Force Microscopy in Action
To observe the microscopic battle, the research team employed a powerful technique called atomic force microscopy (AFM). The imaging was conducted at the London Centre for Nanotechnology at UCL. Unlike conventional microscopes that use light, AFM uses a physical probe—an ultrafine needle just a few nanometers wide—to move across the surface of an object. By “feeling” the contours of the living bacterial cells, the instrument can construct a high-resolution topographical map in real time. This capability allowed the scientists to watch, for the first time, how the surface of a single *E. coli* bacterium changed and degraded during exposure to Polymyxin B.
Visualizing the Breach
The images captured a dramatic sequence of events. Within minutes of introducing the antibiotic, the previously smooth surface of the *E. coli* cell began to contort. Small bumps and bulges erupted across the bacterium’s outer membrane as its structural integrity began to fail. According to Carolina Borrelli, a Ph.D. student involved in the study, “It was incredible seeing the effect of the antibiotic at the bacterial surface in real-time.” These initial protrusions were the first sign that the antibiotic was not just passively damaging the cell but triggering a dynamic and ultimately self-destructive response from the microbe itself.
The Bacterium’s Self-Induced Failure
The most significant finding is that Polymyxin B kills the bacterium by hijacking its own biology. Instead of simply perforating the outer membrane, the antibiotic stimulates the cell to produce and then shed its protective armour. The researchers observed that as the bacterium frantically tried to manufacture new membrane components to repair the damage, it simultaneously lost the very material it was making. This created a futile and catastrophic cycle of production and loss, leading to the formation of gaps in the defensive wall. Once these vulnerabilities appeared, the antibiotic could penetrate the cell and deliver the final, lethal blow.
The Critical Role of the Bacterium’s State
For decades, the prevailing assumption was that antibiotics targeting bacterial armour were effective regardless of the microbe’s condition. However, this study conclusively overturns that belief. The researchers found that Polymyxin B was only effective against bacteria that were metabolically active. When the team exposed dormant, hibernation-like *E. coli* cells to the antibiotic, it had no effect. These dormant bacteria can survive in unfavorable conditions for long periods and “wake up” when circumstances improve, often leading to recurrent infections. Co-senior author Dr. Andrew Edwards of Imperial College London noted the surprise in this finding, stating, “Through capturing these incredible images of single cells, we’ve been able to show that this class of antibiotics only work with help from the bacterium, and if the cells go into a hibernation-like state, the drugs no longer work.”
Implications for Future Drug Development
This detailed understanding of Polymyxin B’s mechanism of action has profound implications for tackling antibiotic resistance. The discovery that the drug is ineffective against dormant bacteria explains a potential reason why infections can persist even after aggressive treatment. The findings suggest that future therapeutic strategies could involve a two-pronged attack. One drug could be used to “wake up” dormant bacteria by providing a food source like sugar, forcing them into an active state. A second drug, like a polymyxin, could then effectively eliminate the now-vulnerable microbes. This approach could lead to more robust treatments that eradicate infections completely, preventing them from recurring.
By revealing the precise vulnerabilities in a bacterium’s defenses, this research provides a blueprint for designing new and improved antibiotics. Scientists can now search for other compounds that exploit this self-destructive shedding mechanism or work to enhance the activity of existing drugs. The high-resolution imaging techniques pioneered in this work serve as a powerful tool for future investigations into the complex interplay between pathogens and the medicines designed to defeat them, opening a new chapter in the ongoing effort to control infectious diseases.