Changing the rules of the race against antibiotic resistance

Pathoblockers: Disarming bacteria instead of killing them

© HZI / Manfred Rohde

At the Helmholtz Centre for Infection Research (HZI), researchers are pursuing such a novel strategy. In the department “Chemical Biology” headed by Prof. Mark Brönstrup, the interdisciplinary team of scientists of the PROTON project is developing a pathoblocker against Staphylococcus aureus. This pathogen is one of the leading causes of antimicrobial resistance-associated deaths worldwide, accounting for more than 500,000 deaths annually.

Unlike conventional antibiotics, the novel drug candidate does not kill the bacteria or inhibit their growth. Instead, it neutralizes a toxin that S. aureus uses to damage host tissues and cause severe disease, effectively disarming the pathogen. Because conventional antibiotics target essential bacterial functions, resistant strains gain an evolutionary advantage. “The race between antibiotics and antibiotic resistance is a race without a finish line,” says Prof. Mark Brönstrup. “Antibiotics that target essential functions will always create selective pressure. Resistance is therefore inevitable; the question is only whether we can slow its emergence and spread.”

Importantly, the compound acts on the toxin after it is secreted by the bacteria. “Crossing the bacterial cell wall and membrane is a major hurdle for many antibiotics”, says microbiologist Dr. Aditya Shekhar, one of the leading scientists in the PROTON team. He illustrates the advantage of their drug candidate with a simple analogy: “We are catching the arrow after it has been shot but before it hits its target.” Additionally, S. aureus appears to lack a direct feedback mechanism that would compensate for the neutralization of this toxin by producing more of it. In other words, the bacteria do not even “notice” that one of their most important weapons has been disabled.

Identification of biomarkers for precision medicine

Pathoblockers are, however, highly specific. Virulence factors differ considerably between bacterial species, meaning that a pathoblocker designed against S. aureus would not work against pathogens such as Pseudomonas aeruginosa. This specificity makes them attractive as precision therapeutics but also means that different pathogens require different pathoblockers.

“We are not only developing the drug itself but also exploring biomarkers that could help clinicians identify the patients most likely to benefit from treatment,” says Shekhar. Such biomarkers could enable more targeted therapies while reducing unnecessary use of broad-spectrum antibiotics.

Closing the gap between discovery and clinical development

Before the PROTON team can start clinical trials with their candidate, it will have to pass critical safety studies. Reaching this stage marks a major milestone and is of the biggest hurdles in antibiotics development. “We are at a critical stage for many antibiotic drug candidates: the transition to clinical development,“ says pharmacist Dr. Dominik Heimann. “We need to close the gap; not just for our project, but for the entire antibiotic pipeline.” 

“Our candidate has the potential to be used either on its own or in combination with existing antibiotics,” Heimann explains. “A key part of our work is identifying the clinical setting in which it can provide the greatest benefit.” Despite the challenges, Heimann sees growing momentum in the field. “We are finally seeing greater awareness of antimicrobial resistance and a broader recognition of the societal value of antibiotics,” he says. The potential of the pathoblocker approach is already being recognized. Mark Brönstrup was one of ten global finalists for the “Science Breakthrough of the Year 2026” award by the Falling Walls Foundation, an acknowledgment of the approach's scientific significance.

Mark Brönstrup concludes: “Antibiotics are far more than treatments for everyday infections. They support large parts of modern medicine, from intensive care to cancer therapy and complex surgery. There will be no single solution to preserving their effectiveness. It will require a combination of innovative drugs, smarter diagnostics and responsible antibiotic use.” Pathoblockers will not solve antimicrobial resistance on their own, but they could change the rules of a race against evolution that humanity cannot afford to lose.