Frogs lead the way in developing new antibiotics

Antibiotic resistance is rising. Infections spread unchecked as old treatments fail. The next solution may come not from labs, but from swamps and forests. Frogs – ancient survivors of earth’s changing ecosystems – have evolved powerful natural defenses. These defenses may hold the key to future antibiotics.

Frogs thrive in environments teeming with microbes. Yet, they rarely suffer infections. That mystery has long intrigued researchers. Could frogs be carrying biological secrets that might save human lives?

​A new study led by Professor Cesar de la Fuente at the University of Pennsylvania believes the answer is yes. His team is tapping into the molecular defenses of frogs to design synthetic antibiotics that may defeat drug-resistant bacteria.​

Frog evolution shaped powerful antibiotics

Frogs have existed for over 200 million years. They have spread across continents and climates, adapting to jungles, rivers, deserts, and subarctic forests. Living in moist, microbe-rich environments, frogs constantly face bacterial threats.

To survive, many species evolved antimicrobial peptides in their skin. These natural compounds kill harmful bacteria on contact. Unlike traditional antibiotics, they do not easily trigger resistance.

One frog species, Odorrana andersonii, has become the focus of research. It produces a peptide known as Andersonnin-D1. Chinese scientists first identified it in 2012.

Despite its strength against bacteria, the peptide clumps together, making it less effective and more toxic. Because of this flaw, it cannot be used in clinical medicine without modification.

Mission to rebuild nature’s blueprints

Professor Cesar de la Fuente’s lab works at the intersection of biology, engineering, and synthetic chemistry. His team looks for inspiration in nature’s forgotten corners.

Their earlier work explored ancient DNA from extinct animals like the woolly mammoth and Neanderthals. They also investigated the human gut microbiome, home to countless natural compounds.

“Each study is motivated by imagining environments where evolution would spur the creation of antibiotics,” said de la Fuente.

“Amphibians live in very microbe-rich environments. They very rarely get infected despite being surrounded by microbes, so they must produce antimicrobial compounds.”

Inspired by this evolutionary logic, the team set out to redesign Andersonnin-D1. The goal was to remove its dangerous tendencies while keeping its bacterial-fighting power.

Improving frog antibiotics in the lab

Using structure-guided design, the researchers altered the chemical structure of Andersonnin-D1. This approach allows experts to make small, deliberate changes to a molecule’s sequence and observe the effects.

Marcelo Torres is a research associate in the de la Fuente lab and co-author of the paper.

“With structure-guided design, we change the sequence of the molecule. And then we see how those mutations affect the function that we are trying to improve,” said Torres.

This method generated several synthetic peptides. These versions kept the strong antimicrobial effect but avoided the clumping that caused toxicity in the original.

Each design aimed for maximum precision, producing molecules more suitable for real-world use.

Putting the molecules to the test

Designing new frog-based antibiotics is only the beginning. To prove their value, the synthetic peptides had to succeed in rigorous lab tests.

The team exposed the molecules to a range of harmful bacteria. The results were promising. In preclinical models, the peptides matched the strength of polymyxin B – a last-resort drug used when others fail.

More importantly, these synthetic antibiotics showed low toxicity. They left human cells unharmed and did not disrupt beneficial gut bacteria. This makes them more targeted and less harmful than many existing drugs. The lab tested the peptides in both simple and complex bacterial communities.

“Those experiments are very difficult to set up because you need to grow different bacteria at once,” says de la Fuente. “We had to come up with the specific ratio of each bacterium to have a sustained community.”

These community-based models better reflect the conditions of real infections in the human body.

Steps toward clinical use

If additional studies continue to show strong results, the team will prepare for Investigational New Drug (IND) enabling studies.

These tests assess safety and efficacy before a drug can be submitted to the U.S. Food and Drug Administration. Only after passing these stages can the peptides move into clinical trials involving human patients.

“We are excited that frogs – and nature in general – can inspire new molecules that could be developed into antibiotics,” said de la Fuente. “Thanks to the power of engineering, we can take those natural molecules and turn them into something more useful for humanity.”

This line of research represents a fusion of evolutionary biology and advanced engineering. It shows how careful study of nature’s own defenses can guide the creation of life-saving medicines.

Nature’s role in innovation

The research was conducted at the University of Pennsylvania’s School of Engineering and Applied Science. It was supported by funding from organizations such as the National Institutes of Health (NIH), the Defense Threat Reduction Agency (DTRA), Procter & Gamble, and the AIChE Foundation.

The study is not just about frogs or antibiotics. It reflects a larger movement in science. Instead of only inventing new molecules from scratch, researchers are increasingly exploring the solutions that evolution already tested over millions of years.

Nature, shaped by survival, often creates molecules more elegant and efficient than anything built by human hands.

In this case, one frog’s molecular defense may lead to a major medical breakthrough. As the world searches for new antibiotics, it may be ancient animals – and the researchers who study them – that help protect our future.

The study is published in the journal Trends in Biotechnology.

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