Promising new antibiotic reveals its secrets

New antibiotic

Researchers are working on a promising new antibiotic: ibezapolstat. This drug, developed by Acurx Pharmaceuticals, is currently being tested in large clinical trials for intestinal infections. The early results are encouraging.

Associate Professor Wiep Klaas Smits explains: "Ibezapolstat targets a specific enzyme, PolC, which bacteria need to produce new DNA. PolC is found only in a certain group of bacteria and not in humans, making the antibiotic very specific. Unlike some antibiotics, ibezapolstat only kills bacteria with PolC, leaving many beneficial intestinal bacteria unharmed. This reduces the risk of side effects. Until very recently, however, we didn't know exactly how the antibiotic worked."

Ice cold

Thanks to cryo-electron microscopy at the Center for Electron Nanoscopy (NeCEN), led by Professor Meindert Lamers, researchers were able to unravel ibezapolstat’s mode of action. Researcher Mia Urem explains: “Cryo-electron microscopy uses a highly advanced microscope to capture high-resolution images of life’s tiniest building blocks at extremely low temperatures. This allows us to observe the interaction between the antibiotic, DNA, and PolC.”

The hook

Urem continues: “We discovered that the structure of the antibiotic is not flat, as previously thought, but has a hook that sticks straight up. With this hook, the antibiotic anchors itself to PolC, preventing the bacteria from creating new DNA and multiplying.”

The antibiotic (illuminating gold) attaches to the bacterial DNA and prevents binding of PolC. Click to enlarge picture. Image made by Ella Maru Studio. 

Smits explains: “Compare it to a bicycle light powered by a dynamo. Without the antibiotic, the wheel (PolC) turns, and light is produced (new DNA). The antibiotic acts like a stick between the spokes, blocking the wheel and preventing the production of light.”

Further tweaking

Now that researchers know how ibezapolstat works, they can continue tweaking the antibiotic to create better variants. Urem elaborates: “Ibezapolstat works very well in the intestine but has difficulty reaching the rest of the body. By making small changes to its chemical structure, we hope to create even better antibiotics that can be taken up by the body. Consequently, this type of antibiotic could then also be used to treat infections outside the intestine.”

Low risk of resistance

An important advantage of ibezapolstat is that it is entirely synthetic. It does not occur naturally, so bacteria have never encountered it before. Smits explains: "Most current antibiotics are modified forms of older antibiotics. They interfere with the same process as their predecessors. Bacteria are already familiar with these tricks, so resistance can often develop more easily. They have never seen ibezapolstat before. This reduces the risk of resistance tremendously. So far, no resistance has been found in the clinical studies of intestinal infections. More importantly, patients did not experience recurrent infections, something that often occurs with other antibiotics."

Joining forces

This research is a prime example of how academic and pharmaceutical partners work together to develop new antibiotics. Smits adds: “Thanks to fundamental research, such as unraveling how ibezapolstat works at the molecular level, we can develop new drugs in a more targeted way. State-of-the-art techniques like cryo-electron microscopy play a pivotal role in this. Together, we are combining knowledge and technology to take important steps in the fight against one of the biggest threats to public health.”

The results of this research were recently published in the prestigious scientific journal Nature Communications. This collaborative project was co-financed by a PPP subsidy awarded by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.