A faster search for antibiotics turns up a promising lead

The goal was to build a faster way to search for new antibiotics. Their search turned up something unexpected.

FIU biochemistry professor Fenfei Leng and a group of researchers set out to develop the first high-throughput screening method specifically designed to identify compounds that can poison bacterial DNA gyrase, an enzyme that bacteria need to survive. While testing this new method, the researchers identified Pyr-AMC — a previously unrecognized compound that could provide a starting point for developing future antibiotics. The discovery comes as growing antibiotic resistance is increasing the urgency to find new ways to fight bacterial infections.

“Because gyrase poisons are very rare, we hope to discover new classes of them that can be developed into future antibiotics,” Leng said. “A High-Throughput Screening method allows us to rapidly identify these rare gyrase poisons from libraries containing thousands or millions of compounds.”

Every time bacteria grow and divide, DNA gyrase helps untangle and organize DNA so it can be copied correctly. Normally, DNA gyrase briefly cuts DNA strands and then quickly seals them back together. Leng and his team found that Pyr-AMC can trap the DNA gyrase while the DNA is cut, leaving the bacteria unable to repair the damage. As broken DNA builds up, the bacteria cells die.

Scientists have been designing antibiotics to attack DNA gyrase for decades. Fluoroquinolones — a class of antibiotics that also targets DNA gyrase — have been among the most effective and widely used antibiotics. But as bacteria have become increasingly resistant to them, researchers have been searching for new DNA gyrase poisons.

While Pyr-AMC is not yet powerful enough to become an antibiotic, the discovery gives researchers a new type of DNA gyrase poison to build on.

“To improve its potency, we need medicinal chemists to synthesize Pyr-AMC analogs,” Leng said. “Most importantly, securing research funding for this project is essential to move this work forward.”

While more research is needed to determine whether Pyr-AMC itself could become an antibiotic, researchers say the discovery demonstrates how the new screening method can uncover rare DNA gyrase poisons that may serve as starting points for future treatments.

The study was recently published in Nucleic Acids Research.