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Researchers find a new way to tackle drug-resistant infections
Bacteria have spent decades evolving resistance to virtually every antibiotic we have thrown at them. To stay ahead, new drugs must hit targets that existing antibiotics have never touched. A research team at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) has now developed a series of synthetic drug candidates that do exactly that: By blocking an essential molecular supply system, these molecules cut off the bacteria's essential vitamins supply and starve them to death. The team published its findings in two studies back to back in the Journal of Medicinal Chemistry.
Like all living cells, bacteria need vitamins to survive and cause infection. Unlike humans, many bacteria rely on specialized membrane transporters — called energy-coupling factor transporters, or ECF transporters — to actively and efficiently import vitamins from their surroundings into the cell. Block these transporters, and the bacteria run out of essential nutrients and die. What makes ECF transporters particularly attractive as a drug target is that human cells do not have them. A drug designed to block these transporters would therefore attack the bacteria while leaving human cells largely unaffected, substantially reducing the risk of side effects. A research team led by Prof. Anna Hirsch, head of the “Drug Design and Optimisation“ department at HIPS, has now succeeded in developing exactly such a drug candidate. HIPS is a site of the Helmholtz Centre for Infection Research (HZI) in collaboration with Saarland University.
The starting point for both studies was a synthetic molecule identified in earlier work by the same group as an inhibitor of ECF transporters. The problem: Stability tests in liver microsomes showed that this early candidate broke down too quickly to be viable as a drug. In the first study, the researchers synthesized a large number of variants of the original molecule and systematically assessed their pharmaceutical properties. This led to candidates that are not only more potent against resistant bacteria but also stable enough to show favorable stability in liver microsome assays. "The tricky part of optimizing this compound class was that potency and stability worked against each other for a long time — modifications that improved one property tended to compromise the other. The turning point came when we started introducing heterocyclic building blocks that addressed both properties at once," says Dr Mostafa Hamed, responsible scientist of the publication. The researchers also demonstrated that the new generation of molecules can successfully combat bacterial infections in insect and zebrafish larvae, providing the first confirmation of their activity in living organisms.
A simultaneously published study tackled a more fundamental question: Can bacteria find an alternative route to import the vitamins they need, if the transporter is blocked? This matters because such a workaround would be a plausible resistance mechanism available to the bacteria. To find out, the team used a gene-silencing technology called CRISPR interference to switch the ECF transporter genes in Streptococcus pneumoniae — one of the world's leading causes of pneumonia — on and off at will. The result was clear: Bacteria with silenced transporter genes became significantly more vulnerable to the experimental compounds, while bacteria carrying extra gene copies responded less sensitively. "What strikes me most about these findings is the conservation of the target. We looked at Streptococcus strains from around the world — isolated from blood, cerebrospinal fluid, and lung fluid of infected patients — and the ECF transporter genes are nearly identical across all of them. That is unusual. It means our approach may be effective not just against a single strain, but potentially against the entire species," says Dr Eleonora Diamanti, first author of the second publication. In a mouse model of lung infection, one of the most promising drug candidates reduced the bacterial burden in the lungs tenfold compared to the untreated control group. Particularly encouraging: No resistant bacterial variants emerged over the course of the experiments, giving reason to hope that a future antibiotic based on this approach may be less prone to resistance development.
Together, the two studies provide the first evidence that ECF transporters are a viable and druggable target for the development of new antibiotics. The team's next steps are to further improve the potency of the drug candidates and to develop strategies for increasing compound concentrations at the site of infection. "ECF transporters have been known to biologists for years, but the drug-discovery community largely overlooked them because they were considered too difficult to target. I believe these two studies together make a strong case that it is worth continuing to invest time and effort in developing drugs against this target," says Anna Hirsch.
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/en
Helmholtz Centre for Infection Research:
Scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig and other locations in Germany study bacterial and viral infections and the body's defense mechanisms. They have in-depth expertise in natural product research and its use as a valuable source for novel anti-infectives. As a member of the Helmholtz Association and the German Center for Infection Research (DZIF), the HZI conducts translational research to lay the foundations for the development of novel therapies and vaccines against infectious diseases. http://www.helmholtz-hzi.de/en
Contact:
Dr. Yannic Nonnenmacher
Scientific Strategy Officer
Phone +49 681 98806 4500
yannic.nonnenmacher@helmholtz-hips.de
Ioulia Exapicheidou, Aleksei Tsarenko, Lena Zeller, Hamza Ibrahim, Carole Baumann, Atanaz Shams, Patrick A. Hoffmann, Yue Li, Andreas M. Kany, Jennifer Hermann, Dirk J. Slotboom, Rolf Müller, Andrea Volkamer, Mostafa M. Hamed, Eleonora Diamanti, Anna K. H. Hirsch: Hit-to-Lead Optimization of Energy-Coupling Factor (ECF) Transporter Inhibitors as Novel Antibiotic. Journal of Medicinal Chemistry (2026); https://doi.org/10.1021/acs.jmedchem.5c02721
Eleonora Diamanti, Amelieke J.H. Cremers, Yue LiIoulia Exapicheidou, Carole Baumann, Paddy Gibson, Atanaz Shams, Louise Martin, Rouven Becker, Inda Setyawati, Lucie Zeimetz, Jörg Haupenthal, Matthias Witschel, Dirk J. Slotboom, Jennifer Herrmann, Katharina Rox, Mostafa M. Hamed, Jan-Willem Veening, Anna K. H. Hirsch: Targeting the Energy-Coupling Factor Transporters: A Novel Antibiotic Drug Target in Streptococcus pneumoniae. Journal of Medicinal Chemistry (2026); https://doi.org/10.1021/acs.jmedchem.5c03638
https://www.helmholtz-hzi.de/en/media-center/newsroom/news-detail/starving-bacte... HZI press release
https://www.helmholtz-hips.de/en/news-events/news/detail/news/starving-bacteria-... HIPS press release
HIPS researchers identify novel targets for antibiotics
Source: Lucia Bernhardt
Copyright: HIPS/Lucia Bernhardt
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HIPS researchers identify novel targets for antibiotics
Source: Lucia Bernhardt
Copyright: HIPS/Lucia Bernhardt
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