(Nanowerk Spotlight) Antibiotic resistance is emerging as one of the most pressing health challenges of the 21st century. As bacteria develop mechanisms to evade conventional drugs, treatments that were once reliable are becoming ineffective. This growing crisis has forced scientists to rethink how antibiotics are developed, moving beyond the limitations of traditional drugs and exploring advanced technologies that offer new ways to combat bacterial infections.
Antibiotics usually work by targeting specific bacterial functions, such as proteins, cell walls, or genetic processes. However, bacteria evolve quickly, developing defenses that render many traditional antibiotics ineffective. While recent advances like modified peptides or synthetic molecules have shown promise, they often remain ineffective against multidrug-resistant (MDR) bacteria or fail to prevent resistance from emerging over time. To tackle these challenges, researchers are turning to nanomaterials – substances that can be engineered at the atomic level to disrupt bacterial processes in ways that bacteria find much harder to resist.
Scientists in the Czech Republic have taken an innovative step in this direction by developing a material that leverages atomic-scale design to counter bacterial resistance. Their research, published in Advanced Materials (“Single Atom Engineered Antibiotics Overcome Bacterial Resistance”), introduces a novel antibacterial agent known as NGA-Mn, or nitrogen-doped graphene acid embedded with manganese ions. This material is not only highly effective against a broad spectrum of bacteria, including multidrug-resistant strains, but also addresses one of the biggest obstacles in antibiotic development: the rapid evolution of bacterial resistance.
a) Scheme of the NGA-Mn synthesis (carbon – dark gray; oxygen – red; nitrogen – blue; manganese – magenta). b) Atomic contents of the nitrogen doped-graphene (NG) after its treatment with nitric acid (NGA) and after immobilization of Mn2+ ions (NGA-Mn). (Image: Adapted from DOI:10.1002/adma.202410652, CC BY)
Historically, the discovery of antibiotics transformed medicine, turning once-deadly infections into treatable conditions. But bacteria, especially dangerous ones like Staphylococcus aureus and Escherichia coli, have proven remarkably adept at evolving mechanisms to resist these treatments. Standard antibiotics often target specific bacterial proteins or functions, and bacteria can quickly mutate to protect these vulnerable spots. Worse, bacteria can share these resistance traits, passing on the ability to survive even the strongest drugs. The rise of “superbugs,” which are resistant to multiple antibiotics, has thus become a global health concern, with predictions that by 2050, drug-resistant infections could cause millions of deaths each year.
Faced with this challenge, researchers have been seeking new ways to disrupt bacterial growth without triggering resistance. This is where this new work comes in. The team’s approach hinges on single-atom engineering, a cutting-edge technique that allows scientists to control the behavior of individual atoms within a material. By carefully selecting and arranging atoms, materials can be designed with highly specific properties. In this case, the researchers used graphene, a well-known material composed of a single layer of carbon atoms, as the basis of their design.
Graphene has been studied extensively for its remarkable strength, conductivity, and stability. But its application in antibiotics has been limited – on its own, it does not have significant antibacterial properties. To change this, the team modified the graphene by doping it with nitrogen atoms and attaching functional groups made of carboxyl, which is a type of oxygen-based molecule. These changes created a unique chemical structure capable of interacting with manganese ions in a highly controlled way. When manganese, an essential micronutrient in many biological processes, is anchored to the graphene in this specific configuration, it becomes a potent antibacterial agent.
The result of this engineering process is NGA-Mn, a material that behaves very differently from typical antibiotics. Unlike traditional drugs that enter bacterial cells and interfere with internal processes, NGA-Mn operates externally. The manganese ions on the graphene surface bind to the outer membrane of bacteria in a highly coordinated manner, disrupting vital functions. This multimolecular binding essentially prevents bacteria from maintaining their cell walls, a process crucial for their survival. As a result, the bacteria die off without the need for the material to penetrate the cell or interfere with specific proteins.
One of the key advantages of NGA-Mn is its broad spectrum of activity. In tests, the material was effective against both Gram-positive and Gram-negative bacteria, two major classes that differ in their membrane structures. These include notorious pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and multidrug-resistant Escherichia coli. These bacteria are responsible for some of the most difficult-to-treat infections, particularly in hospital settings where antibiotic resistance is widespread.
The researchers measured the minimum inhibitory concentration (MIC) of NGA-Mn—the lowest concentration needed to completely inhibit bacterial growth. For most bacteria tested, the MIC was as low as 4 to 16 milligrams per liter, a range that matches or even outperforms many of the strongest available antibiotics. Even more promising, after 30 generations of bacterial exposure to NGA-Mn, no significant resistance had developed. This is a remarkable finding, as most bacteria develop resistance to traditional antibiotics much faster. In a comparative study, the team showed that bacteria exposed to silver nanoparticles, another powerful antibacterial agent, developed resistance within just nine generations.
The absence of resistance is largely due to how NGA-Mn operates. Since it binds to multiple molecules on the surface of the bacterial membrane, rather than targeting a specific protein, it’s much harder for bacteria to mutate in a way that would evade the material’s effects. Traditional antibiotics often target a single protein, and even a small genetic mutation can make that protein unrecognizable to the drug. But the wide-reaching mechanism of NGA-Mn makes it far more difficult for bacteria to evolve a workaround.
Another significant advantage of NGA-Mn is its safety. In medicine, one of the challenges of developing new antibacterial agents is ensuring they are toxic to bacteria but not to human cells. In their study, the team demonstrated that NGA-Mn is highly cytocompatible, meaning it does not harm human cells at concentrations far higher than those needed to kill bacteria. Tests on human lung and skin cells showed that the material was tolerated at levels more than 25 times higher than its effective antibacterial dose. This selectivity is crucial for any future clinical application, as it suggests that NGA-Mn could be used in medical treatments without damaging healthy tissues.
The research also included tests in a live animal model to explore the potential real-world application of NGA-Mn. In a mouse model of infected skin wounds, NGA-Mn was applied topically, and its effectiveness was compared to that of norfloxacin, a commonly used antibiotic. The results were encouraging: NGA-Mn not only healed the infected wounds but did so as effectively, if not more, than norfloxacin, even in cases where the bacteria were resistant to the drug.
Looking ahead, the potential applications of NGA-Mn are broad. Its ability to work against a wide range of bacteria, including multidrug-resistant strains, makes it a promising candidate for treating infections that have become difficult or impossible to manage with existing antibiotics. Its high level of safety also suggests potential for use in topical treatments, wound care, and perhaps even systemic applications, though more research would be needed to confirm its effectiveness in other types of infections.
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