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Researchers at the HIPS decipher novel mode of action of natural product antibiotic
The development and spread of antibiotic resistance represents one of the greatest threats to global health. To overcome these resistances, drugs with novel mode of action are urgently needed. Researchers at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) have now uncovered the mode of action of a promising class of natural products – the chlorotonils. These molecules simultaneously target the bacterial cell membrane and the bacteria’s ability to produce proteins, enabling them to break through resistance. The team published its findings in the journal Cell Chemical Biology.
The more frequently antibiotics are used, the faster pathogens evolve mechanisms to evade their effects. This leads to resistant pathogens against which common antibiotics are no longer effective. To ensure that effective treatments for bacterial infections remain available in the future, antibiotics that target different bacterial structures than currently approved drugs are essential. One such candidate was discovered by HIPS researchers back in 2008 in the soil bacterium Sorangium cellulosum: the natural product class of chlorotonils. These compounds exhibit strong activity against hospital pathogens Staphylococcus aureus and Enterococcus faecium, as well as the malaria pathogen Plasmodium falciparum, and act via a previously unknown mechanism. The HIPS is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.
In the newly published study, researchers led by Dr. Jennifer Herrmann and Prof. Rolf Müller uncovered the novel mode of action of chlorotonils. They demonstrated that chlorotonils attack bacterial pathogens with a combined approach, unlike most antibiotics. On one hand, they bind to membrane lipids, destabilizing the bacterial membrane. Additionally, they inhibit two enzymes involved in cell wall and protein synthesis. First author Dr. Felix Deschner, a postdoc in Müller’s department “Microbial Natural Products”, explains exactly how chlorotonils exert their effect: “When chlorotonil binds to the cell membrane, potassium ions can leak uncontrollably out of the cell. This throws the cell’s internal environment off balance – the membrane’s electrical potential changes, osmotic pressure drops rapidly, and essential cellular processes are disrupted.” In combination with the inhibition of the phosphatase YbjG and the methionine aminopeptidase MetAP, the bacterial cell’s functions are so severely impaired that cell death ultimately occurs.
“Initially, we had promising efficacy studies, but the target structure and exact mode of action were unclear,” says Deschner. To address these questions, the researchers conducted extensive experiments and created a “profile” of the molecule. “Through this, we discovered that chlorotonils bind directly to lipids, thereby influencing the membrane potential. This was unexpected, as it represents a rarely observed antibiotic mechanism,” Deschner explains. The alteration of membrane potential results in immediate activity, which also explains chlorotonils’ rapid bactericidal effect. Their direct interaction with membrane lipids also makes it more difficult for bacteria to develop resistance mechanisms against chlorotonils. If an antibiotic targets a specific enzyme, bacteria can either produce more of it or structurally alter it to protect themselves. These options don’t apply to lipids. Only through mutations in the lipid efflux system, which controls the composition of the cell membrane, were more resistant bacterial strains identified. Understanding the resistance mechanism against an antibiotic is crucial for developing strategies to counteract it – for example, through combination therapies or structural modifications of the compound.
“Our findings show that chlorotonils pursue an entirely new mode of action and simultaneously target multiple critical structures in the bacterial cell,” says Herrmann. “This makes them potential game-changers in the fight against multidrug-resistant pathogens and opens up opportunities to systematically search for other agents with similar mechanisms.” The researchers are currently working on optimizing the efficacy and safety of chlorotonils. In parallel, under the GO-Bio initial program, they are developing chlorotonils into a drug for the treatment of malaria.
This press release is also available on our website: https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/chlorotonil-ga....
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and its other sites in Germany are engaged in the study of bacterial and viral infections and the body’s defence mechanisms. They have a profound expertise in natural compound research and its exploitation as a valuable source for novel anti-infectives. As member of the Helmholtz Association and the German Center for Infection Research (DZIF) the HZI performs translational research laying the ground for the development of new treatments and vaccines against infectious diseases. http://www.helmholtz-hzi.de/en
Helmholtz Institute for Pharmaceutical Research Saarland:
The Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken was founded jointly by the HZI and Saarland University in 2009. Scientists at HIPS develop and employ experimental and computational approaches to provide new active substances against infectious diseases, optimise them for use in humans and investigate how they can best be transported to their site of action in the human body. A special focus of the institute is on microbial natural products from soil bacteria and the human microbiota as well as innovative medicinal chemistry-driven approaches. http://www.helmholtz-hips.de
Contact at HIPS:
Dr. Yannic Nonnenmacher
Scientific Strategy Officer
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
Campus Building E8 1, 66123 Saarbrücken
Phone +49 681 98806 4500
yannic.nonnenmacher@helmholtz-hips.de
Felix Deschner, Dietrich Mostert, Jan-Martin Daniel et al.: Natural products chlorotonils exert a complex antibacterial mechanism and address multiple targets. Cell Chemical Biology. 2025. DOI: 10.1016/j.chembiol.2025.03.005
https://www.helmholtz-hips.de/en/news-events/news/detail/news/chlorotonil-game-c...
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