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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 supply of essential vitamins and starve them to death. The team published its findings in two studies in the Journal of Medicinal Chemistry.
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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 Anna Hirsch, head of the "Drug Design and Optimization" department at HIPS, has now succeeded in developing exactly such a drug candidate. HIPS is a site of the Helmholtz Center for Infection Research (HZI) in collaboration with Saarland University.
Balancing potency with stability
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 for 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.
Testing a possible escape route
A study published simultaneously 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.
Early signs in animal models
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 encouragingly, 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 developing resistance.
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 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 Hirsch.
More information: Ioulia Exapicheidou et al, Hit-to-Lead Optimization of Energy-Coupling Factor (ECF) Transporter Inhibitors as Novel Antibiotic, Journal of Medicinal Chemistry (2026). DOI: 10.1021/acs.jmedchem.5c02721
Eleonora Diamanti et al, Targeting the Energy-Coupling Factor Transporters: A Novel Antibiotic Drug Target in Streptococcus pneumoniae, Journal of Medicinal Chemistry (2026). DOI: 10.1021/acs.jmedchem.5c03638
Provided by Helmholtz Association of German Research Centres
This story was originally published on Phys.org.
