Infections with antibiotic-resistant bacteria are among the leading causes of death worldwide. Researchers have now identified a potential new antibiotic against which no resistances are known to date. The active ingredient Clovibactin comes from a soil bacterium that has not previously been cultivated in the laboratory. It attacks the basic building blocks of the bacterial cell wall and was able to effectively combat infections with Staphylococcus aureus in experiments on mice. From the researchers' point of view, further developed variants of the antibiotic could be suitable for use in humans.
Various bacteria and fungi naturally produce antimicrobial substances to prevail against enemies. Depending on the mechanism of action, these natural antibiotics can inhibit the reproduction of bacteria or kill them, for example by dissolving their cell walls. Over time, however, resistance develops both in nature and in the medical use of antibiotics. In particular, multi-resistant germs, against which a large number of known antibiotics are ineffective, are responsible for millions of deaths worldwide every year. In the search for new antibiotics against which there is no resistance yet, researchers are turning to synthetic substances. On the other hand, they look for previously undiscovered active ingredients in nature. However, one problem is that many potentially relevant microorganisms are difficult to cultivate in the laboratory.
Robust against resistance development
A team led by Rhythm Shukla from the University of Utrecht in the Netherlands has now discovered a potential new antibiotic in a bacterium previously thought to be uncultivable. "We urgently need new antibiotics to fight bacteria that are becoming increasingly resistant to most clinically used antibiotics," says Shukla's colleague Markus Weingarth. The team found what they were looking for in the soil bacterium Eleftheria terrae subspecies carolina from a soil sample in North Carolina in the USA. Using a specially designed chip that allows the bacteria to be grown in their natural soil environment, the team managed to cultivate E. terrae and isolate its antibacterial substance: the antibiotic clovibactin.
"Because clovibactin was isolated from bacteria that could not previously be grown, pathogenic bacteria have never seen such an antibiotic and have not had time to develop resistance," explains Weingarth. Through studies on different cell lines, the researchers found that clovibactin attacks three different molecules that are essential for building the cell wall of bacteria. "The multi-target attack mechanism of Clovibactin simultaneously blocks bacterial cell wall synthesis at different sites," explains co-author Tanja Schneider from the University of Bonn. "This improves the activity of the drug and significantly increases its robustness against the development of resistance."
Cage around the target structure
According to the results, clovibactin binds with high specificity to so-called pyrophosphate groups, an unchangeable component of the target molecules. Since the antibiotic encloses the pyrophosphate group like a cage, the researchers chose the name clovibactin based on the Greek word klouvi for cage. After several Clovibactin molecules have bound, they combine to form stable fibrils that enclose the target molecules for as long as it takes to kill the bacteria. "Because clovibactin only binds to the unchanging, conserved part of its targets, the bacteria will have a much harder time developing resistance to it," says Weingarth. "In fact, we did not observe any resistance to clovibactin in our studies."
The research team carried out initial efficacy tests with mice that had been infected with the bacterium Staphylococcus aureus. Clovibactin killed the bacteria just as well as the reserve antibiotic vancomycin, which is currently one of the most important agents against severe bacterial infections. "Clovibactin therefore has potential for the development of improved therapeutics that kill bacterial pathogens without developing resistance," says Weingarth. However, before the antibiotic can actually be used in humans, further studies on safety and effectiveness must follow. "There is still a long way to go before it can be launched on the market," says Schneider.
Source: Rhythm Shukla (University of Utrecht, Netherlands) et al., Cell, doi: 10.1016/j.cell.2023.07.038