Solving antibiotic resistance requires a new perspective

Antibiotics can force benign bacteria to evolve resistance. Scientists must develop strategies to prevent these off-target effects.

By Harrison Luba

In 2003, a 21-year-old football player who seemed healthy suddenly died. The cause was a bacterial infection called MRSA (methicillin-resistant Staphylococcus aureus). What started as a simple pimple quickly became fatal. Within 12 hours, Ricky Lannetti had passed away. Doctors tried many antibiotics, but none could stop the deadly bacteria.

Nearly two decades later, antimicrobial resistance (AMR) has become a global crisis. AMR is linked to 5 million deaths each year, and some researchers warn that number could double by 2050. Even with billions spent on antibiotics, bacteria continue to outpace our efforts. What was once a medical miracle, a cure for infections that had long claimed lives, is now slipping out of our hands. The pipeline for new antibiotics is drying up, and we need to look for other options.

The fight against AMR cannot rely on new antibiotics alone. For decades, scientists have raced to stay ahead of bacterial evolution, but microbes adapt too well. We must invest in strategies that prevent resistance from emerging in the first place. This requires addressing conditions that let resistance spread as well as addressing systemic issues that make AMR research so difficult.

Antibiotic drugs are still the foundation of infection treatment. Unfortunately, their widespread use can unintentionally perpetuate the problem. While these drugs kill most infectious bacteria, a few may carry mutations that allow them to survive. These surviving mutants reproduce, passing on their resistance to future generations. The more we use antibiotics, the more we fuel the very resistance we are trying to fight. A sustainable solution to antimicrobial resistance will not eliminate antibiotics entirely, but instead will focus on using them effectively, efficiently, and responsibly.

Most AMR funding goes towards developing new drugs. A 2024 report from the World Health Organization shows that nearly $2 billion is spent each year on AMR research and development. Much of that investment prioritizes new antibiotics, rather than addressing the root causes of resistance. The result is a constant arms race between humans and microbes. We seem set to lose unless we change our strategies.

One promising approach is identifying where resistance is most likely to emerge so that we can intervene before it does. David Kennedy is an Associate Professor of Biology at Penn State University. He studies how infectious diseases evolve and how resistance develops. His research suggests that we must fundamentally rethink our approach to AMR. In a 2024 study, Kennedy and his team looked at various pathogens, antibiotics, and transmission types to identify factors linked to high and low resistance.

Their findings confirmed that bacteria acquired in hospitals are especially prone to resistance. The study also showed that indirect transmission, for example through water, had the highest chance of developing resistance. These results suggest that resistance is not solely due to antibiotic use. It is also influenced by how and where infections are spread.

“Instead of trying to come up with new things, we should figure out where antimicrobial resistance has not emerged in the past,” Kennedy says. “Can we study the cases where resistance hasn’t been a problem?”

Kennedy’s work reframes the AMR challenge. Instead of asking how to kill resistant bacteria, he asks what we can learn from where bacteria fail to develop resistance. If we can understand the dynamic factors that may make resistance unlikely to develop, we can try to replicate those factors in other scenarios. The key to beating resistance might not be to fight harder, but to fight smarter.

Kennedy’s ecological insights show that we may be able to use antibiotics in ways that do not accelerate resistance. This means not only choosing the right drug, but also understanding how the drug will interact with different bacteria. Surprisingly, resistance often develops not in the bacteria we are targeting, but in those we are not.

“For many of our most concerning antibiotic resistance problems, the drug exposure is off-target,” says Dr. Robert Woods, Associate Professor of Internal Medicine at the University of Michigan Medical School. His point is simple, yet important: antibiotics often go to parts of the body where they aren’t needed. This causes bacteria that are not even causing illness to adapt and potentially develop resistance.

An example of this problem is vancomycin, which is a last-resort antibiotic used for infections that are resistant to other drugs. Vancomycin treats infections in the bloodstream, but some of the drug is then excreted into the gut. There, it meets Enterococcus faecium, a species of bacteria linked to resistance. These bacteria are not causing any symptoms, yet they’re being exposed to this powerful drug. This exposure creates selective pressures that favor resistant strains of bacteria, allowing them to flourish and spread. In effect, every dose of vancomycin risks breeding the next generation of superbugs.

Woods and his team published research in July, 2025 on what researchers are calling “anti-antibiotics.” They developed nanocrystals that neutralize vancomycin once it hits the gastrointestinal tract. This approach stops the drug’s effects in the gut, minimizing the risk of resistance while keeping the drug’s therapeutic effect in the bloodstream.

While Woods’ study focused on vancomycin, the concept of anti-antibiotics could potentially be extended into other drug classes. Many other antibiotics are also excreted into off-target sites, such as in the urine. If similar neutralizing technologies could be developed for these antibiotics, we could dramatically reduce the selective pressures that fuel resistance in other bacterial populations. Anti-antibiotics are a smarter delivery system that preserve the efficacy of antibiotics, yet do not contribute to resistance.

This method is promising because it does not target the bacteria directly. Instead, it targets the conditions that allow resistance to evolve. It represents a change from reactive treatment to proactive resistance prevention.

Even promising innovations face systemic challenges. A 2023 paper in the Journal of Antimicrobial Chemotherapy explained why researchers had to stop developing DAV-132. This drug was a promising option. It was designed to protect bacteria in the gut from being exposed to antibiotics. The idea was original and scientifically sound, but the therapy never made it through the clinical trial process.

A big hurdle in getting treatment approval for a clinical trial is meeting the Food and Drug Administration’s rigid criteria. The developers needed to show that DAV-132 might offer health benefits; however, protecting the gut microbiome is not officially seen as one. Microbiome health affects immunity, digestion, and even mental health. But outdated rules and guidelines have prevented researchers from using it to justify clinical trial approval.

To address this, researchers had to find a group with high antibiotic exposure and clear clinical outcomes. Researchers selected patients receiving chemotherapy for leukemia. This group has a higher risk of Clostridioides difficile infections,a bacterial species that often develops resistance. The study suffered from a small sample size, a high cost, and a high dropout rate due to the severity of the illness. Because of these factors, research into DAV-132 was stopped short.

The story of DAV-132 was not just about one drug’s failure. Instead, it highlights a broader systemic issue: the difficulty of conducting research on AMR. To support research on preventing resistance, we need to change how clinical benefit is defined and evaluated. Protecting the microbiome needs to be recognized as a legitimate therapeutic goal, or the fight against AMR becomes nearly impossible.

Some critics believe the threat of AMR is exaggerated. They note that resistant infections represent only a small part of total infections. In addition, they suggest that we may never fully defeat AMR; bacteria will never stop evolving. These are valid concerns, but the AMR crisis will only continue to get worse without swift and strategic action. The cost of inaction is far greater than the risk of overreaction.

Antimicrobial resistance is not a distant threat. It is a growing crisis that has already claimed millions of lives and shows no signs of slowing down. To confront AMR, we must focus on preventing resistance before it starts. It is imperative to reconsider what counts as clinical success, so that we can support research into therapies that keep antibiotics effective. We need to ask not only how to kill bacteria, but also how to stop resistance from evolving in the first place.

“We’re hoping to get to a stage where we can stably use a collection of antibiotics without this constant increase in resistance,” says Woods. His vision is a blueprint for the future. A future with effective antibiotics relies on stopping resistance before it starts. If we want to use antibiotics effectively, we must see resistance as preventable, not inevitable. Our window for acting is narrowing fast.