Leiden researchers discover how a promising antibiotic works against intestinal infections

Researchers at Leiden University Medical Center (LUMC) have mapped the mechanism of action of a promising new antibiotic. Under a cryo-electron microscope, researchers Mia Urem et al. observed that the drug attaches to bacterial DNA with a kind of molecular hook.

The drug in question, ibezapolstat from Acurx Pharmaceuticals, is still undergoing extensive clinical testing for its effectiveness against intestinal infections. It is considered a promising antibiotic because it is not based on existing drugs but instead has an entirely unique mechanism of action, meaning that bacteria have not yet developed resistance to it.

Until recently, however, it was not known exactly how ibezapolstat works. Using a cryo-electron microscope, researchers from Leiden mapped out its mechanism. In this technique, the research material is rapidly cooled to temperatures far below zero. Because of this fast cooling process, water molecules do not form crystals, allowing the biological structures to remain clearly visible.

The researchers discovered that, due to its molecular structure, the antibiotic can attach like a hook to the enzyme PolC, which normally plays a key role in DNA replication. When PolC is blocked, the bacterium can no longer reproduce, and the infection subsides. The scientists describe their findings in the journal Nature Communications.

In addition to revealing how the drug works, the microbiologists also studied how bacterial resistance to ibezapolstat might develop. They identified several critical sites in the PolC enzyme where mutations could potentially reduce the antibiotic’s effectiveness. By understanding how resistance can emerge, the researchers write, it may be possible to prevent these drugs from losing their potency too quickly.