Novel Synthetic Antibiotics Against Drug-Resistant Pathogens

Frogs have thrived for hundreds of millions of years, adapting to nearly every ecosystem on Earth—from lush tropical rainforests to chilly subarctic woodlands. Along the way, they've developed remarkable defense systems, including antimicrobial compounds that help them survive in microbe-rich, humid environments.

Now, researchers believe these natural defenses could hold the key to fighting antibiotic-resistant bacteria in humans.

In a recent study published in Trends in Biotechnology (Cell Press), César de la Fuente, Presidential Associate Professor at the University of Pennsylvania, and his team report the development of synthetic peptides—lab-designed antibiotics inspired by compounds secreted by a South Asian frog species.

Nature’s Antibiotic Toolkit

The study builds on earlier work from de la Fuente’s lab, which has uncovered promising antibiotic candidates in unexpected sources like the DNA of extinct woolly mammoths and Neanderthals, as well as the human gut microbiome.

“We look for environments where evolution has pushed organisms to develop potent antimicrobial strategies,” says de la Fuente. “Amphibians, for instance, live surrounded by microbes but rarely suffer from infections. That tells us their bodies must produce powerful antimicrobial compounds.”

Back in 2012, researchers in China discovered that Odorrana andersonii—a frog known for its distinctive scent—produces a peptide called Andersonnin-D1 with antimicrobial activity. But in its natural form, the peptide tends to clump together, reducing its efficacy and increasing toxicity, making it unsuitable for therapeutic use.

Enhancing Nature’s Blueprint

In the new study, de la Fuente’s team applied a method called structure-guided design to modify the peptide’s sequence at a molecular level. These subtle structural tweaks helped eliminate the limitations of the original compound while enhancing its antibacterial properties.

“We change the sequence and then observe how those modifications influence the function we’re aiming to improve,” explains Marcelo Torres, a research associate and co-author.

After two rounds of structure-guided design, the team tested the new synthetic peptides against a range of harmful bacteria. In preclinical models, the peptides performed comparably to polymyxin B—a last-resort antibiotic—but with a key advantage: they were less toxic to human cells and spared beneficial gut bacteria.

Testing in Realistic Microbial Environments

Unlike many studies that test compounds in isolated bacterial cultures, this research evaluated the peptides in mixed microbial communities, more closely mimicking the environments where infections actually occur.

“Setting up those experiments is tough,” de la Fuente notes. “You need to grow different bacteria simultaneously and carefully balance their ratios to keep the community stable.”

The results are promising. If further preclinical testing continues to show strong outcomes, the team plans to move forward with Investigational New Drug (IND)-enabling studies, which are required before seeking FDA approval to begin clinical trials.

For de la Fuente, the work highlights the untapped potential of nature in shaping the future of medicine.

“We’re excited that frogs—and nature more broadly—can inspire entirely new molecules,” he says. “With the tools of engineering, we can refine those natural compounds and turn them into real solutions for human health.”